WO2022093871A1

WO2022093871A1 - Sars-c0v-2 inactivation by ethacridine

Info

Publication number: WO2022093871A1
Application number: PCT/US2021/056717
Authority: WO
Inventors: Raul Andino-Pavlovsky; Xiaokun Shu; Petr LIDSKIY; Yinghong XIAO; Xiaoquan LI
Original assignee: University of California Berkeley; University of California San Diego UCSD
Current assignee: University of California Berkeley; University of California San Diego UCSD
Priority date: 2020-10-26
Filing date: 2021-10-26
Publication date: 2022-05-05
Anticipated expiration: 2023-04-26

Abstract

Herein, existing and approved drugs that were not previously used as antiviral agents are disclosed that may be readily repurposed to treat viral infections, including COVID-19. In a primary implementation, ethacridine and derivatives thereof are utilized in methods of treating viral infections, including COVID-19. Drug delivery devices for administering ethacridine are provided. Also disclosed are novel reporters of SARS-CoV-2 Mpro activity that may be utilized to identify novel agents for treating viral infections such as COVID-19.

Description

Title: SARS-CoV-2 Inactivation by Ethacridine

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS: This application claims the benefit of priority to United States Provisional Application Serial Number 63/105,846 entitled “SARS-CoV-2 Inactivation by Ethacridine,” filed October 26, 2020, the contents which are hereby incorporated by reference.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT: This invention was made with government support under grant numbers R01 AI040085 and P01AI091575 awarded by The National Institutes of Health. The government has certain rights in the invention.

[0003] Background and Summary of the Invention

[0004] The worldwide outbreak of the respiratory disease CO VID-19 is caused by the coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). SARS-CoV-2 is an RNA betacoronavirus of the family Coronaviridae .

[0005] SARS-CoV-2 contains a single-stranded positive-sense RNA genome encapsulated within a membrane envelope. Its genomic RNA is approximately 30kb. The genome of SARS-CoV-2 can be split into two main regions that contain as many as 14 open reading frames (ORFs). The first region, containing ORFla/b, makes up about two-thirds of the genome. After coronavirus attachment and entry into the host cell, the viral genomic RNA is released. The first region of the genomic RNA is translated to form polyproteins, which undergo extensive proteolytic processing, resulting in the release of numerous proteins essential for viral propagation. A critical actor in this process is a 3 -chymotrypsin-like protease (3CLpro, referred as the main protease, Mpro).

[0006] Thus, Mpro plays a central and critical role in the lifecycle of the coronavirus and represents a potential drug target. Accordingly, there is a need in the art for new agents that inhibit Mpro and which may be used as antiviral drugs.

[0007] As of the date of the present disclosure, SARS-CoV-2 infection continues to sicken and kill thousands of people daily. There remains a need in the art for agents that can be used in the prevention and treatment of CO VID-19. Furthermore, given the urgency of the pandemic, there is a need in the art for the identification of existing drugs that are known to be safe and well tolerated by patients which can be quickly repurposed and deployed against SARS-CoV-2.

[0008] Meanwhile, other viral pathogens collectively sicken or kill millions of people each year in regional and seasonal outbreaks. Additionally, in an interconnected world, new viral pathogens such as zoonotic pathogens, may arise at any time and spread quickly to afflict vulnerable populations. Accordingly, there is a need in the art for novel therapeutic methods to prevent, treat, and contain existing and future viral diseases.

[0009] Summary of the Invention.

[0010] The inventors of the present disclosure developed a novel screening platform for the identification of Mpro inhibitors. In one aspect, the scope of the invention encompasses novel compositions and associated methods of use for the identification of novel inhibitors of viral proteases such as Mpro. The assay provides the art with a facile detection agent having large dynamic range suitable for the high throughput screening of novel inhibitors of Mpro.

[0011] By the Mpro sensor of the invention, 1622 FDA-approved drugs were screened, leading to the identification of several existing drugs that inhibit Mpro activity. Among the agents identified as Mpro inhibitors, several were further tested for their anti-SARS-CoV-2 activity and nine showed significant antiviral activity at 5 pM.

[0012] The most potent agent, ethacridine showed outstanding antiviral activity, further validated by studies in ACE2 expressing human lung epithelial cells and human primary nasal epithelial cells, wherein very high antiviral potency was observed. Additional investigation, as disclosed herein, demonstrated that ethacridine inhibits SARS-CoV-2 mainly by inactivating viral particles, including an ability to inactivate the virus before binding to cells and after it has budded from host cells. The surprising and unexpected viral inactivation activity of ethacridine appears to be stronger than its Mpro inhibitory activity alone, and provides the art a powerful agent to inhibit viral spread between cells and between host organisms.

[0013] Advantageously, ethacridine is a regulatory-approved therapeutic in many jurisdictions, having been long used as an antiseptic and in other treatment contexts, with a good history of safety and tolerance, inexpensive manufacture, and ready availability. [0014] Accordingly, in one aspect, the scope of the invention encompasses the novel use of ethacridine as an antiviral agent, for example, for the inactivation of viral particles. In another aspect, the scope of the invention encompasses the novel use of ethacridine as an antiviral agent for the prevention and treatment of CO VID-19. In another aspect, the scope of the invention encompasses the utilization of ethacridine derivatives as antiviral agents, including for the prevention and treatment of COVID-19.

[0015] The scope of the invention further encompasses the novel use of additional repurposed drugs as inhibitors of viral protease activity, including SARS-CoV-2 Mrpo activity. The repurposed agents may be used in the he prevention and treatment of viral infections such as COVID-19. The repurposed agents include ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfin.

[0016] Brief Description of the Figures

[0017] Fig 1. Fig. 1 depicts the normalized ratio of Mpro activity in drug (10 pM) vs DMSO-incubated cells. The Mpro activity was determined as FlipGFP fluorescence normalized to mCherry. The ratio of Mpro activity was calculated by normalizing Mpro activity with that of cells treated with DMSO. Data are mean (n = 5).

[0018] Fig. 2. Fig. 2 depicts quantitative analysis of viral titer from plaque assays on Vero E6 cells treated with each drug at 5 pM. Data are mean (n = 3). *** p < 0.001.

[0019] Fig. 3A, 3B, 3C, 3D, 3E, and 3F. Fig. 3A-3F depict dose-response and cell-toxicity curve of Mpro-inhibiting drugs (and for comparison, remdesivir) against SARS-CoV-2 by plaque assays. The percentage of relative infection was determined by the ratio of infection rate of SARS-CoV-2 treated with each drug divided by that of DMSO control. EC50 and CC50 are represented as mean (n = 3). Fig. 3 A: Simeprevir; Fig. 3B: Cinacalcet; Fig. 3C: Ethacridine; Fig. 3D: ABT-199 (Venetoclax); Fig. 3E: Hydroxyprogesterone; Fig. 3F: Remdesivir.

[0020] Fig. 4A, 4B, and 4C. Fig. 4A depicts Plaque-reduction assay (P value <0.0001 ). Fig 4B depicts the normalized immunofluorescence of NP (n= 4, ***: p value < 0.001). Fig. 4C depicts the normalized immunofluorescence of spike (n=3, value < 0.0001). [0021] Fig. 5A, 5B, 5C, and 5D. Fig. 5A-D depict the virucide effect of ethacridine on SARS-CoV-2. Effects of ethacridine on the viral particles of SARS-CoV-2 were examined using plaque-reduction assay at 37C (Fig. 5A and 5B) or at room temperature (Fig. 5C and 5D). SARS-CoV-2 (MOI = 100) was mixed with ethacridine for 1 or 2 hours, before being added to infect Vero E6 cells. Data are mean (n = 3).

[0022] Fig. 6A, 6B, and 6C. Fig. 6A depicts ethacridine blocking SARS-CoV-2 in primary human nasal epithelial cells, quantified infection ratio based on anti-Spike protein (S) or anti- Nucleocapsid protein (N) staining. Data are mean (three biological replicates). **: p value < 0.01. Fig. 6B depicts quantitative analysis of viral titer by plaque assay in the human cells A549 that stably express ACE2, wherein SARS-CoV-2 was pre-incubated with ethacridine (5 uM) for Ihr, followed by plaque assay on the human A549 cells stably expressing human ACE2. Fig. 6C depicts antiviral effects of ethacridine (infection ratio) in the HNE cells, wherein SARS-CoV-2 was incubated with DMSO or 5 //M ethacridine. The mixture was then added to the HNE cells (n=3, infection ratio of the ethacridine-treated sample = Q,p<0.0001).

[0023] Detailed Description of the Invention.

[0024] Ethacridine and Uses Thereof. The scope of the invention encompasses the novel use of various existing therapeutic compositions discovered by the inventors of the present disclosure to have efficacy against viral pathogens. The invention encompasses a general method of treating viral infection in a subject in need of treatment therefor by the administration of a therapeutically effective amount of a selected repurposed antiviral agent.

[0025] In a primary implementation, the antiviral agent is ethacridine. Ethacridine is known as 7-ethoxyacridine-3,9-diamine, CAS Registry Number 442-16-0, Etakridin, or 2-Ethoxy- 6,9-diaminoacridine. The molecular structure of ethacridine is:

[Structure

[0026] Ethacridine is known in the art as an antibiotic agent, and is particularly effective against gram-negative bacteria. Commercially, it is often formulated as ethacridine lactate, for example, sold as RIVANOL(TM), and has been used topically as well as in injected and oral forms. Ethacridine is well tolerated and has very low toxicity to mammals, for example, at dosages of up to 20mg/kg. Advantageously, ethacridine is approved for use by the regulatory authorities of various jurisdictions, for example, the United States Food and Drug Administration.

[0027] As disclosed herein, the inventors of the present disclosure have surprisingly discovered that ethacridine is a potent anti-viral composition. As used herein, an antiviral agent or composition is a composition of matter that effectively inactivates viral particles of one or more types of virus. Ethacridine is an antiviral agent having high efficacy against SARS-CoV-2, inhibiting SARS-CoV-2 with an EC50 of about 0.08 zM. Ethacridine may inactivate viruses by various modes of action: inactivating viral particles prior to cell entry; inhibiting the SARS-CoV-2 3 -chymotrypsin-like protease (3CLpro) which is the main protease (MPro) of the virus; intercalating and binding viral RNA nucleotides, for example, via pi-stacking, hydrogen bonding and electrostatic interactions; and blocking viral binding to host cells by interactions with viral proteins.

[0028] The methods of the invention further encompass the use of ethacridine derivatives. With regards to any therapeutic agent enumerated herein, it will be understood that reference to such agent further encompasses derivatives of the enumerated agent. As used herein a “derivative” of an enumerated agent comprises a modified form of the agent or a chemically similar composition of matter which retains the therapeutic capabilities of the enumerated composition. Derivatives may comprise one or more modifications and substitutions of the core of the or backbone of the enumerated molecule and modifications or substitutions of the side chains of the enumerated molecule. Derivatives may be designed and selected to optimize any number of factors, for example, chemical modifications that alter the charge, hydrophobicity or hydrophilicity of the molecule, modifications that increase resistance to breakdown in the body, modifications that impart improved bioavailability, modifications that improve solubility, stability, or shelf life, modifications that increase manufacturing convenience, and other modifications, as known in the art.

[0029] Furthermore, it will be understood that reference to an enumerated composition, e.g., ethacridine, will encompass its tautomeric forms, its stereoisomers, its enantiomers, and its polymorphs. [0030] Certain implementations of the invention encompass the administration of an ethacridine derivative. A derivative of ethacridine may be any composition of matter comprising a modified form of ethacridine, analog of ethacridine, or molecule with chemical similarity to ethacridine which retains some or all antiviral activity of ethacridine, or which has improved antiviral activity, for example, having ethacridine’ s ability to inhibit SARS- CoV-2 viral particles. In one embodiment, the ethacridine derivative is a molecule comprising an acridine or substituted derivative thereof. In one embodiment, the ethacridine derivative is selected from Table 1.

[0031] In one embodiment, the ethacridine derivative comprises the composition:

[Structure 2]: wherein Ri and R2 may be any of: an amine, hydrogen, or a group selected from acylamino, dialkylamino, cycloalkylamino, azacycloalkyl, alkylcycloalkylamino, aroylamino, diarylamino, arylalkylamino, aralkylamino, alkylaralkylamino, arylaralkylamino, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkoxy, perfluoro alkoxy, mercapto, alkylthio, arylthio, aralkylthio, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, hydroxysulfonyl, amidosulfonyl, dialkylamidosulfonyl, arylalkylamidosulfonyl, formyl, acyl, aroyl, alkyl, alkylene, alkenyl, aryl, aralkyl, vinyl, or alkynyl groups; and wherein R3 may be any of: an aryl ethyl ether, hydrogen, or a group selected from acylamino, dialkylamino, cycloalkylamino, azacycloalkyl, alkylcycloalkylamino, aroylamino, diarylamino, arylalkylamino, aralkylamino, alkylaralkylamino, arylaralkylamino, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkoxy, perfluoro alkoxy, mercapto, alkylthio, arylthio, aralkylthio, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, hydroxysulfonyl, amidosulfonyl, dialkylamidosulfonyl, arylalkylamidosulfonyl, formyl, acyl, aroyl, alkyl, alkylene, alkenyl, aryl, aralkyl, vinyl, or alkynyl groups. [0032] In a first implementation, the scope of the invention encompasses: a pharmaceutical composition comprising ethacridine or a derivative thereof, for use in a method of preventing or treating a viral infection. In a related implementation, the scope of the invention encompasses a method of preventing or treating a viral infection in a subject in need of treatment, comprising administration to the subject of a therapeutically effective amount of a pharmaceutical composition comprising ethacridine or a derivative thereof. In another implementation, the scope of the invention encompasses the use of ethacridine or a derivative thereof in the manufacture of a medicament for the prevention or treatment of a viral infection.

[0033] In one implementation, the scope of the invention encompasses: a pharmaceutical composition comprising ethacridine or a derivative thereof, for use in a method of preventing or treating coronavirus infection. In a related implementation, the scope of the invention encompasses a method of preventing or treating a coronavirus infection in a subject in need of treatment, comprising administration to the subject of a therapeutically effective amount of a pharmaceutical composition comprising ethacridine or a derivative thereof. In another implementation, the scope of the invention encompasses the use of ethacridine or a derivative thereof in the manufacture of a medicament for the prevention or treatment of coronavirus infection.

[0034] In a primary implementation, the scope of the invention encompasses: a pharmaceutical composition comprising ethacridine or a derivative thereof, for use in a method of preventing or treating CO VID-19. In a related implementation, the scope of the invention encompasses a method of preventing or treating COVID-19 in a subject in a subject in need of treatment, comprising administration to the subject of a therapeutically effective amount of a pharmaceutical composition comprising ethacridine or a derivative thereof. In another implementation, the scope of the invention encompasses the use of ethacridine or a derivative thereof in the manufacture of a medicament for the prevention or treatment of COVID-19.

[0035] Additional Repurposed Antiviral Agents. The scope of the invention further encompasses methods of preventing or treating a viral infection by the administration of one or more selected agents discovered by the inventors of the present disclosure to have antiviral activity. The inventors of the present disclosure have discovered that certain existing therapeutic molecules have an inhibitory effect on the activity of viral proteases necessary for viral propagation, such as the Mpro protease of SARS-CoV-2. The repurposed antiviral agents include: ABT- 199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfin, and therapeutically effective derivatives of the foregoing.

[0036] In one implementation, the scope of the invention encompasses: a pharmaceutical composition comprising an agent selected from the group consisting of: ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, verteporfin, and a derivative of any of the foregoing, for use in a method of inhibiting the activity of a viral protease, e.g. SARS-CoV-2 Main viral protease. In a related implementation, the scope of the invention encompasses a method of inhibiting the activity of a viral protease, e.g. SARS-CoV-2 Main viral protease, in a subject at risk of or suffering from a viral infection, comprising administration to the subject of a therapeutically effective amount of a pharmaceutical composition comprising an agent selected from the group consisting of ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, verteporfin, and a derivative of the foregoing. In another implementation, the scope of the invention encompasses the use of an agent selected from the group consisting of ABT- 199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfin, or a derivative of the foregoing, in the manufacture of a medicament for inhibiting the activity of a viral protease, e.g. the SARS-CoV-2 Main viral protease (Mpro).

[0037] In one implementation, the scope of the invention encompasses: a pharmaceutical composition comprising an agent selected from the group consisting of: ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfin, or a derivative of the foregoing, for use in a method of preventing or treating a viral infection, e.g. a coronavirus infection, e.g., CO VID-19. In a related implementation, the scope of the invention encompasses a method of preventing or treating a viral infection, e.g. a coronavirus infection, e.g., COVID-19, in a subject, comprising administration to the subject of a therapeutically effective amount of a pharmaceutical composition comprising an agent selected from the group consisting of ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfm, or a derivative of the foregoing. In another implementation, the scope of the invention encompasses the use of an agent selected from the group consisting of ABT-199, artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, hydroxyprogesterone, ivermectin, nifuroxazide, sertaconazole, simeprevir, sulconazole, and verteporfm, or a derivative of the foregoing, in the manufacture of a medicament for preventing or treating a viral infection, e.g. a coronavirus infection, e.g., COVID-19.

[0038] Subjects. The methods of the invention are applied in treatment of a subject. As used herein, a “subject” may comprise any animal. In a primary embodiment, the subject is a human, for example, a human patient. In some embodiments, the subject is a subject having a viral infection or in need or treatment for a viral infection, for example, a coronavirus infection, for example, COVID-19. In some embodiments, the subject is a subject having symptoms of a viral infection, for example, a coronavirus infection, e.g., COVID-19. In some embodiments, the subject is a subject at risk of a viral infection, for example, COVID- 19, for example, by suspected or actual exposure to viruses. In some embodiments, the subject is a medical practitioner or other medical staff at risk of viral infection, such as COVID-19 by virtue of sustained exposure to infected persons.

[0039] In other embodiments, the subject may comprise a test animal, veterinary subject, or other non-human animal, for example, a mouse, rat, dog, cat, cow, horse, pig, or non-human primate. In some implementations, the subject comprises cultured cells, as in an experimental or drug screening process.

[0040] Viruses. The various methods of the invention are directed to the treatment of viral infections. In alternative implementations, the methods are applied in the treatment of an infection caused by a non-viral pathogen such as a bacteria, protozoan, or other infectious agent.

[0041] In one embodiment, the virus is a coronavirus, i.e. a virus of the family Coronaviridae . In a primary embodiment, the virus is SARS-CoV-2. Reference to SARS- CoV-2 made herein encompasses all known and future variants of SARS-CoV-2, including, for example, any of: alpha, beta, gamma, delta, epsilon, eta, zeta, iota, theta, and kappa variants; variants comprising the B.1.427, B.1.429, B.1.1.7., and B.1.617.2 lineages; and variants comprising the D614G, N501 Y, E484K, or L452R mutants.

[0042] In other embodiments, the virus may comprise another coronaviruses, including for example, 229E, NL63 (alpha), OC43 (beta), HKU1 (beta), MERS-CoV (the causative agent of Middle East respiratory syndrome (MERS)) or SARS-CoV (the causative agent of severe acute respiratory syndrome (SARS)).

[0043] In other embodiments, the virus may be selected from the group consisting of: adeno-associated virus, BK polyomavirus, cowpox virus, coxsackievirus, eastern equine encephalitis virus, Ebolavirus, encephalomyocarditis virus, Epstein-Barr virus, Hanta virus, a hepatitis virus (for example, hepatitis A virus, hepatitis B virus , or hepatitis C virus), a herpes virus, Human immunodeficiency virus (HIV), papillomavirus, a rhinovirus, an influenza virus (including, for example, influenza A virus, influenza B virus, and influenza C virus), Marburg virus, measles virus, poliovirus, a rotavirus (including rotavirus A, rotavirus B, and rotavirus C), a rhinovirus, rubella virus, a vaccinia virus, varicella-zoster virus, West Nile virus, yellow fever virus, and Zika virus. In some embodiments, the virus is an RNA virus, for example, any virus containing a containing a single-stranded positivesense genome.

[0044] Treatment. Certain methods of the invention are directed to subjects having a viral infection, at risk of a viral infection, or otherwise in need of treatment for a viral infection. As used herein, “treatment” encompasses achieving any therapeutic effect with regards to a viral infection. Treatment may encompass ameliorating, reducing, curing or otherwise therapeutically intervening against the symptoms, morbidity, infectivity, and risk of mortality associated with the infection of a subject by the selected pathogen. In various aspects, treatment may encompass prevention of infection by a selected pathogen, reducing the severity of symptoms, reducing the duration of the infection, etc. In various embodiments, treatment encompasses the inactivation of viral particles, wherein the agent inhibits one or more viral processes which underlie infection, viral propagation, and spread. For example, viral inactivation may encompass the inhibition of one or more processes selected from the group consisting of: docking of the virus to target extracellular moieties, membrane fusion, endocytosis of viral particle contents, viral replication, post-translational processing of viral transcripts, packaging of virions, lysis of the host cell, transmission of virions to other cells, viral shedding, or the spread of virions to other subjects. [0045] Administration of Antiviral Agents. The methods of the invention encompass the administration of a selected antiviral agent, e.g., ethacridine, to a subject. Administration may be by any selected route.

[0046] In one embodiment, the antiviral agent, e.g., ethacridine, is delivered by injection. In one embodiment, the agent is delivered by intravenous injection. In other embodiments, the antiviral agent is delivered by any of intravenous, intraperitoneal, intramuscular, or subcutaneous injection.

[0047] In other embodiments, the selected route of administration is aerosol administration, e.g. wherein the therapeutic agent is delivered to the airway of the subject. For example, the selected antiviral agent, e.g. ethacridine, may be suspended in a liquid or deposited on solid particulates and then is subsequently dispersed into the airway of the subject by a gaseous carrier or propellant. Aerosol delivery advantageously enables delivery of therapeutic agents directly to cells of the airway wherein many viruses, for example, SARS-CoV-2, infect cells of the respiratory tract. As used herein, the “airway” may encompass any one or more of the following: the nasal cavity; sinuses; the nasopharynx; the oropharynx; the larynx; the trachea; the lungs or portions thereof, including the bronchi; the bronchioles, the alveolar ducts, and the alveolar sacs; and airway cells such as epithelial cells, goblet cells, ciliated cells, basal cells, and secretory cells.

[0048] In alternative embodiments, the pharmaceutical compositions of the invention are administered by other modes of delivery, for example, oral, transmucosal, transdermal, or topical delivery.

[0049] Dosages. The therapeutic agents of the invention will be administered in therapeutically effective amounts comprising one or more administered doses. One of skill in the art may determine the dosage by taking into account the physical, chemical, and pharmacological (e.g. ADMET) properties of the pharmaceutical composition comprising the selected antiviral agent, the route of administration, and the therapeutic need. Exemplary dosages may include, for example, cumulative daily dosages of 10 ng to 50 mg/kg body weight per day, for example: 10 ng, 50 ng, 100 ng, 200 ng, 500 ng, 1 pg 5 pg, 10 pg, 15 pg, 20 pg, 25 pg, 30 pg, 40 pg, 50 pg, 60 pg, 70 pg, 80 pg, 90 pg, 100 pg, 200 pg, 300 pg, 400 pg, or 500 pg, 1 mg, 5 mg, 10, mg, or more mg per kg body weight per day. Administration may be daily, including multiple daily administrations (e.g. 2, 3, 4, 5, or more), or multiple times per week. In one embodiment, the dose is an amount sufficient to induce a concentration of the selected antiviral agent in target cells (or in the extracellular area of such cells) of at least 0.01 pM, 0.05 pM, 0.08 pM, 0.10 pM, 0.20 pM, or 0.50 pM.

[0050] Pharmaceutical Compositions. The methods of the invention encompass treatment of a subject by administration of a therapeutically effective amount of a pharmaceutical composition comprising a selected antiviral agent, e.g., ethacridine.

[0051] Various therapeutic agents are named herein. Reference to an enumerated agent, e.g. ethacridine, will be understood to encompass salts and solvates of the agent, particularly pharmaceutically acceptable salts. Pharmaceutically acceptable salts may be selected by one of skill in the art according to considerations such as solubility, bioavailability, ionic balance, and other factors. In some embodiments, the salt may be a salt comprising a hydrochloride, sulfate, sodium, anionic, cationic, inorganic base, organic base, inorganic acid, organic acid, amino acid, or gluconate salt. Exemplary salts of ethacridine, or other antiviral agents enumerated herein, and their derivatives include, for example, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, sodium, stearate, succinate, sulfate, tartrate, teoclate, or tosylate salts.

[0052] The pharmaceutical compositions of the invention may further encompass conjugates between the selected antiviral agent and one or more functional moieties, for example, a moiety selected to facilitate drug delivery and retention, targeting to specific tissues or cell types, and conjugates with additional therapeutic agents.

[0053] The pharmaceutical compositions of the invention may further encompass the selected antiviral agent in combination with one or more additional compositions. For example, the formulations of the pharmaceutical composition may facilitate storage, administration, and efficient delivery to target cells or tissues of the body. The pharmaceutical compositions of the invention may comprise any number of pharmacologically compatible carriers, excipients, diluents, buffers, preservatives, colorants, flavoring agents, or release formulations. [0054] The pharmaceutical compositions of the invention may be formulated in particular dosage forms compatible with the selected route of administration. In one embodiment, the selected route of administration is aerosol administration. Pharmaceutical compositions for aerosol delivery may include solutions or dry powders, for example, wherein the antiviral agent is dissolved in a solvent or present in or on particles comprising a carrier material, for example, particles in the range of 1-10 pm. Exemplary carriers include carbohydrates, lipids, polymeric materials, and other aerosol delivery carriers known in the art.

[0055] In other implementations the pharmaceutical compositions of the invention are formulated for other routes of administration. In one embodiment, the pharmaceutical compositions of the invention comprise liquid solutions, such as for oral ingestion or injection; suspensions and emulsions; granules, tablets, or capsules; gels, creams, and other dosage forms known in the art. In one embodiment, the pharmaceutical compositions of the invention may be formulated as nanoparticles containing or functionalized with the selected therapeutic agent, for delivery by nanoparticle-based delivery methods. In one embodiment, the pharmaceutical compositions comprises the selected therapeutic agent admixed with a polymeric material for timed release elution of the therapeutic agent in the body, for example, drug eluting hydrogels. In one embodiment, the therapeutic agent is coated onto an implant or drug-eluting device.

[0056] In various implementations, the pharmaceutical compositions of the invention comprise combination products, wherein a selected antiviral agent of the invention, e.g. ethacridine, is administered in combination with one or more additional therapeutic agents. In one embodiment, the one or more additional active agents comprises an antiviral agent. In one embodiment, the one or more additional active agents comprises an agent administered to subjects being treated for a respiratory disease, such as COVID-19. Exemplary additional agents include, for example, remdesivir, dexamethasone, favilavir, ebselen, therapeutic antibodies, such as anti-SARS-CoV-2 antibodies, peramivir, zanamivir, oseltamivir phosphate, baloxavir marboxil, interferon-a, cidofovir, ribavirin, fomivirsen, protease inhibitors, nucleoside analogs, nucleotide analogs, drugs that serve as competitive substrates for viral DNA polymerases, and inhibitors of viral ion channel M2 protein or neuraminidase.

[0057] In some implementations, the selected therapeutic agent and the one or more additional active agents are admixed in a single formulation. In an alternative implementation, the combination products of the invention comprise a kit, wherein the kit comprises separate dosage forms of the selected antiviral agent, e.g. ethacridine, and the one or more additional active agents, packaged or sold together.

[0058] Drug Delivery Devices. In some implementations, the scope of the invention encompasses aerosol delivery devices comprising an apparatus which holds and facilitates delivery of a pharmaceutical composition of the invention. The devices may further comprise mechanical components capable of delivering a controlled dosage of such pharmaceutical composition to the airway of the subject. The delivery may be accomplished by pumps, vaporizing elements such as heaters or vibrational energy sources, or by the use of compressed gases and propellants, as known in the art. In one embodiment, the device comprises a dry powder inhaler. In one embodiment, the device comprises a metered-dose inhaler. In one embodiment, the device comprises a nebulizer. In one embodiment, the device comprises a device for delivering agents via a mechanical ventilator, such as a pressurized metered dose inhaler, adaptive aerosol device, or vibrating mesh nebulizer configured for use with a mechanical ventilator.

[0059] In a primary implementation, the drug delivery devices of the invention are constituted for delivery of pharmaceutical compositions comprising ethacridine or derivatives thereof. In various embodiments, the drug delivery device may comprise any of: a dry powder inhaler loaded with a pharmaceutical compositions comprising ethacridine or a derivative thereof; a metered-dose inhaler loaded with a pharmaceutical compositions comprising ethacridine or a derivative thereof; a nebulizer loaded with a pharmaceutical compositions comprising ethacridine or a derivative thereof; or an adaptive aerosol device loaded with a pharmaceutical compositions comprising ethacridine or a derivative thereof.

[0060] Additional Uses of Antiviral Agents. In some embodiments, the scope of the invention encompasses an article of manufacture functionalized with one or more selected antiviral agents enumerated herein, for example, ethacridine. For example, such items may be used for the prevention of viral infection, for example, to prevent SARS-CoV-2 infection. Examples include coatings on textiles, for example wherein the therapeutic agent is incorporated into a carrier material (e.g. solution, suspension or emulsion, particle, etc.) that is sprayed onto, coated onto, impregnated into, or otherwise present in or on the textile, and wherein such textiles may be components of items such as face masks, gloves, gowns, or other items of Personal Protective Equipment (PPE), such as used by medical personnel or for general use. Similar coatings may be applied to medical equipment, such as ventilator components, treatment surfaces, and other items wherein viral spread is a threat.

[0061] Mpro Protease Reporter. In another aspect, the scope of the invention encompasses novel tools and associated methods for the assessment of viral RNA processing protease activity, such as SARS-CoV-2 Mpro activity. In SARS-CoV-2 , the main protease Mpro is 3 -chymotrypsin-like protease (3CLpro) , which processes the ppla and pplab polyproteins at 11 conserved sites comprising a conserved cleavage sequence. This processing of the polypeptides ppla and pplab is essential to viroid formation and spread and is a major target in the search for COVID-19 therapeutics. Accordingly, there is a need in the art for screening tools that enable the facile identification of viral protease inhibitors, such as SARS-CoV-2 Mpro inhibitors.

[0062] The inventors of the present disclosure have developed a novel viral protease reporter that may be used screening for viral protease inhibitors such as Mpro inhibitors. The protease reporter is a fusion protein comprising the domains of a fluorescent reporter proteins, wherein one or more domains of the fluorescent protein is configured in a position such that it is not active and protein fluorescence is absent, wherein the inactive domain is configured with a protease cleavage site, such that viral protease activity, e.g. SARS-CoV-2 Mpro activity, if present, liberates the domain to assume an active form, creating a fluorescent signal. In one embodiment, the screening tool is a FlipGFP construct, for example, as described in Zhang et al., 2019. Designing a Green Fluorogenic Protease Reporter by Flipping a Beta Strand of GFP for Imaging Apoptosis in Animals, Am. Chem. Soc. 141 : 4526-4530.

[0063] The viral protease reporter may comprises a fusion protein FlipGFP, wherein one of the eleven beta-strands of a split GFP is flipped. In one embodiment, the split GFP contains two parts: one part contains beta-strands 10 and 11 (i.e. GFP10 and 11), and the other part contains nine other beta-strands and the central alpha helix (i.e. GFP1-9). GFP10-11 contains the highly conserved Glu222 that is essential in catalyzing the chromophore maturation. GFP 1-9 contains the three amino acids that form the chromophore via cyclization, dehydration and oxidation. GFP 10-11 spontaneously binds GFP 1-9 and catalyzes the chromophore maturation, leading to a green fluorescent GFP. In one embodiment, , GFP 10- 11 is “flipped” using heterodimeric coiled coils (for example, E5 and K5) so that the “flipped” GFP10-11 cannot bind GFP1-9 when viral protease activity is absent, and thus little or no fluorescence is generated. Specifically, in one embodiment, the E5 coiled coil may inserted between GFP10 and GFP11, and GFP11 is followed by the K5 coiled coil. A viral protease cleavage sequence, for example, a SARS-CoV-2 Mpro-specific cleavage sequence AVLQSGFR, is inserted between GFP11 and K5. In the presence of active viral proteases, the protease, e.g., Mpro, binds and cleaves the site so that GFP11 is flipped back, and the “activated” GFP10-11 can bind GFP1-9, resulting in bright fluorescence, detectable by appropriate imaging devices, such as fluorescence microscopy devices. In some implementations, the two parts (flipped GFP10-11 and GFP1-9) are linked by a “selfcleaving” peptide, such as 2A. In some embodiments, to normalize the fluorescent signal, the construct further comprises a secondary fluorescent protein, such as red mCherry.

[0064] By the protease reporters of the invention, compositions may be screened to identify inhibitors of viral protease activity, such as SARS-CoV-2 Mpro activity. For example, in one implementation, cells are engineered to express the selected viral protease, e.g., SARS-CoV- 2 Mpro, and the protease reporter construct of the invention. The cells are then cultured and exposed to a putative viral protease inhibitor, wherein protease activity results in cleavage and activation of the fluorescent protein and wherein inhibited protease activity results in reduced activation of the fluorescent signal.

[0065] EXAMPLES.

[0066] Example 1. Ethacridine inhibits SARS-CoV-2 by inactivating viral particles [0067] Rational design of a Anorogenic Mpro activity reporter. To develop an activity reporter of Mpro with a large dynamic range suitable for high-throughput screening (HTS), a GFP -based protease reporter was developed. The FlipGFP reported, as described in Zhang et al. Designing a Green Fluorogenic Protease Reporter by Flipping a Beta Strand of GFP for Imaging Apoptosis in Animals. J Am Chem Soc. American Chemical Society; 2019; 141 : 4526-4530, was adapted, which was designed by flipping one of the 11 beta-strands of a split GFP. Briefly, the split GFP contains two parts: one part contains beta-strands 10 and 11 (i.e., GFP10 and 11), and the other contains nine other beta-strands and the central alpha helix (i.e., GFP1-9). GFP10-11 contains the highly conserved Glu222 that is essential for catalyzing chromophore maturation. GFP 1-9 contains the three amino acids that form the chromophore via cyclization, dehydration and oxidation. GFP 10-11 spontaneously binds GFP 1-9 and catalyzes the chromophore maturation, leading to green fluorescence. To design an Mpro activity reporter, GFP10-11 was “flipped” using heterodimeric coiled coils (E5 and K5) so that the flipped GFP10-11 cannot bind GFP1-9 when Mpro is inactive, and thus, no or little fluorescence is detected. An Mpro-specific cleavage sequence was used between GFP11 and K5. In this way, when Mpro cleaves the proteolytic site, GFP11 is flipped back, allowing GFP10-11 to bind GFP1-9, resulting in bright fluorescence The reporter was named FlipGFP^Mpro. To normalize the fluorescence, a red fluorescent protein mCherry was added within the construct via a “self-cleaving” 2A peptide. To determine if FlipGFP^Mpro serves to report on Mpro activity of SARS-CoV-2 in living cells, ACE2, a SARS-CoV2 receptor, was expressed in HEK293-FlipGFP^Mpro cells. Next, cells were infected with SARS-CoV-2, and at 24 hours post-infection, cells were analyzed by immunofluorescence using antibodies against double-stranded RNA (dsRNA) and FlipGFP^Mpro green fluorescence. The green fluorescence of the sensor, normalized by the co-expressed mCherry, was 63% greater in the coronavirus- infected cells than in mock-infected cells. Infected cells also showed dsRNA fluorescence compared to non-infected (mock) cells without dsRNA staining. These data demonstrate that the utility of FlipGFP^Mpro as a reporter of SARS-CoV-2 Mpro activity in human cells.

[0068] Next, a system for screening Mpro inhibitors was established in living cells by exogenously expressing Mpro in HEK293 cells. Specifically, wild-type Mpro or an inactive Mpro mutant (with catalytic cysteine 145 mutated to alanine) were co-expressed in this cell line. The green fluorescence of FlipGFP^Mpro was barely detected in the cells expressing the inactive Mpro/C145A mutant, whereas the red fluorescence of mCherry was observed. On the other hand, strong green fluorescence was detected in the cells expressing Mpro with similar levels of mCherry fluorescence. The green fluorescence of FlipGFP^Mpro, normalized to the red fluorescence of mCherry, revealed an ~60-fold dynamic range between inactive and active Mpro. Furthermore, based on these quantified data, we calculated a Z’ -factor, as described in Zhang and Oldenburg, Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. Journal of Biomolecular Screening. 1999;4: 67-73. pmid: 10838414, which is ~0.8 with Mpro demonstrating that the assay is robust for HTS.

[0069] The FlipGFP^Mpro sensor was not responsive to the TEV protease, and the FlipGFP- based TEV reporter (FlipGFP^TEV) was only activated by TEV but not by Mpro. Thus, FlipGFP^Mpro specifically detects Mpro activity with a large dynamic range, establishing a robust HTS system for screening Mpro inhibitors at a BSL2 level with 60-fold fluorescence change and a robust z’ -factor. Difference of the normalized FlipGFP^Mpro fluorescence in the SARS-CoV-2 infected cells and that in the cells expressing Mpro exogenously suggests that the active Mpro concentration in the cytoplasm of the coronavirus-infected cells is ~100-fold lower than that of the HEK293 cells exogenously expressing Mpro (under a EFla promoter).

[0070] HTS of drugs that inhibit Mpro activity in living cells. Next, a high throughput screen (HTS) of -1600 FDA-approved drugs (20 pM final concentration) was performed. The reporter construct (FlipGFP^Mpro and mCherry) was transfected into HEK293 cells, followed by addition and incubation of the drugs. Green fluorescence normalized to red fluorescence were then calculated. A volcano plot revealed -120 drugs that showed > 50% reduction of Mpro activity with a p-value < 0.001. To confirm this result, the identified -120 drugs were re-screened under similar conditions, the top 15 drugs were surveyed at a lower concentration (10 pM) and it was found that 12 drugs showed >50% reduction of FlipGFP^Mpro fluorescence (normalized by mCherry) at 10 pM concentration (Fig. 1). An IC50 was calculated for each of the 12 drugs. IC50 of six drugs were at 2-6 pM, and the rest were above 6 pM. Lastly, determined cellular viability of these identified drugs in HEK293T cells was determined, which showed that they are not toxic at the concentrations that inhibit Mpro activity.

[0071] Antiviral activity of identified drugs. Next was investigated antiviral activity of selected drugs in Vero E6 cells. The cell monolayers were pretreated with the 12 selected drugs for 3 hours, and then infected with SARS-CoV-2. The cells were further cultivated in the presence of each respective compound at a concentration of 5 pM. After 16 hours of incubation, the culture media samples were collected, and the amount of infectious particles were estimated by plaque assay revealing that 9 of the 12 drugs showed significant antiviral activity at 5 pM. Strong inhibition was detected for ethacridine with 5-6 logs reduction in viral titer, simeprevir ~4-log reduction, ABT-199 -2 -log reduction, hydroxyprogesterone -1- log reduction, cinacalcet ~l-log reduction. Two of the 12 drugs (ivermectin and verteporfin) were cytotoxic at 5-13 pM in Vero E6 cells and excluded from further analysis. As a comparison, the antiviral effect of a reported Mpro inhibitor, ebselen was tested, which showed -2 -log reduction in viral titer. The RdRp inhibitor remdesivir showed ~4-log reduction. [0072] Next, dose-response curves for the top 5 selected drugs were calculated. First, the data revealed that the EC50 of four drugs (simeprevir, cinacalcet, ABT- 199 and hydroxyprogesterone) was 1-3 pM, within a range similar to their IC50 in inhibiting Mpro (Fig. 3 A-3E). This was consistent with the expectation that SARS-CoV-2 replication is inhibited by restricting Mpro activity. By contrast, ethacridine showed outstanding antiviral activity (EC50 ~ 0.08 pM), which is 40-fold lower (i.e. stronger) than its Mpro-inhibiting activity (IC50 ~ 3.54 pM). These data suggest that the antiviral activity of ethacridine is not mainly accounted for by its Mpro-inhibiting activity. Lastly, for comparison, the EC50 of remdesivir -0.52 pM was determined (Fig. 3F) in a side-by-side manner which indicates that ethacridine is more potent than remdesivir.

[0073] Ethacridine inhibits SARS-CoV-2 by inactivating viral particles. To determine how ethacridine inhibits SARS-CoV-2, infectivity of the virus particles after ethacridine treatment was tested with plaque assay, and viral RNA levels using qRT-PCR was also measured. The antiviral effect of ethacridine on different stages of the lifecycle of SARS- CoV-2 was examined, including virus-cell binding, RNA replication, and budding. To test overall effect of ethacridine on virus replication, SARS-CoV-2 particles were pre-incubated with ethacridine (5 pM) or DMSO control for 1 hour. The mixture was then added to Vero E6 cells for viral adsorption at a multiplicity of infection (MOI) at 0.5. Next, the solution was removed and fresh medium added containing ethacridine (5 pM) or DMSO control. Sixteen hours later, supernatant was collected and a plaque assay with overlaid agar without ethacridine or DMSO was conducted to measure viral titer. qRT-PCR was used to measured viral RNA levels in the supernatant and within cells. In this way, three conditions: 1) Control (DMSO + DMSO): the virus and cells were exposed to DMSO and not the drug; 2) The virus and cells were exposed to the drug at all stages, including 1 hour before infection, during replication, and after viral budding (i.e. Eth. + Eth.); 3) The virus and cells were exposed to the drug only after viral entry, during replication, and after budding (i.e. DMSO + Eth.). Lastly, a fourth condition was devloped: a plaque assay was conducted right after pretreatment of SARS-CoV-2 with ethacridine for 1 hr (i.e. Eth. [1 hr]), which determines direct effect of the drug on viral particles.

[0074] When ethacridine was present continuous prior to plaque assay (Eth. + Eth.), viral titers were reduced 3-4 logs, compared with the control (DMSO + DMSO). When ethacridine was added to the Vero cells after viral entry (DMSO + Eth.), similar level of reduced infectivity (3-4 logs reduction in viral titer) was observed. Importantly, when SARS- CoV2 was pre-incubated with ethacridine for 1 hr (Eth. [1 hr]) and followed by plaque assay without drug, 3-4 logs reduction in infectivity was also observed. This result suggests that the drug directly inactivates SARS-CoV2 viral particles. Because of similar-level reduction in infectivity in all of the three conditions, the data strongly suggests that ethacridine inhibits SARS-CoV-2 mainly by inactivating viral particles.

[0075] Viral RNA accumulation in infected cells was investigated next. qRT-PCR measurement revealed no change of viral RNA (vRNA) levels when the drug was added after viral binding and cell entry (DMSO + Eth.) in both the supernatant and the cells. This indicates that the drug had no effect on vRNA replication. As the infectivity of supernatant from “DMSO + Eth” treated samples showed 3-4 logs reduction in plaque assay, these data suggests that ethacridine inhibits SARS-CoV-2 by inactivating the viral particles without effect on vRNA replication. This is consistent with the results of plaque assays for the supernatant samples with 3 different treatments in that showed 3~4 log reduction in infectivity after virions in the supernatant were exposed to the drug before plaque assay.

[0076] Next, when ethacridine was present continuously (i.e. Eth. + Eth.), 4-5 fold reductions were observed in vRNA copies in the supernatant and within cells. Because plaque assay -based measurement of the same conditioned sample (Eth. + Eth.) showed 2400- fold reduction in viral titer, the effect of ethacridine on viral replication (4-5 fold reduction) is about 500-fold smaller than its effect on viral infectivity. This further supports the conclusion that ethacridine inhibits SARS-CoV-2 by inactivating the viral particles. The 4-5 fold reduction of vRNA copies was attributed to reduced viral copy numbers that may bind to the cells, because here the additional step is that the virus were pre-incubated with the drug.

[0077] Thus, the plaque assay and qRT-PCR data show that ethacridine inhibits SARS-CoV- 2 mainly by inactivating viral particles, including the virus before binding to cells and in the supernatant after budding from host cells, with no or little effect on vRNA replication.

[0078] To further investigate the mechanism of ethacridine-based inactivation of the viral particles, immunofluorescence staining and imaging was conducted to determine whether the ethacridine-treated SARS-CoV-2 can bind to the cells. SARS-CoV-2 was treated with ethacridine (5 pM) or DMSO for 1 hour at 37°C. Then the virus was added to cells for adsorption (4°C, 1 hour) at a MOI = 100. Cells were then quickly washed and fixed with 4% PF A. Immunostaining with antibodies against the nucleocapsid protein (N) of SARS-CoV-2 showed strong anti-N fluorescence on the plasma membrane of the cells infected with control virus, but little anti-N fluorescence in cells exposed to ethacridine treated virus. Immunostaining against the Spike protein (S) of SARS-CoV-2 showed the same results (Fig. 4A-4C). Furthermore, to examine whether ethacridine blocks viral binding to cells by perturbing the cellular factors for viral binding such as cellular receptors, cells were pretreated with ethacridine for 3 hours. This was followed by washing and drug removal, immediately prior to addition of SARS-CoV-2. The data showed that viral infection was not affected by these procedures, suggesting that the main effect of the drug is not on the cells, but on the viral particles. These results indicate that ethacridine-treated SARS-CoV-2 cannot bind cells to initiate infection.

[0079] An additional experiment was conducted to confirm results. Ethacridine was mixed with SARS-CoV-2 and the drug/virus mixture was immediately added to the Vero cells (i.e. no preincubation of the drug with the virus). After adsorption for 1 hour (37°C), the cells were overlayed with agar and media for plaque assay. Under this condition, first, the drug was be able to inhibit potential cellular factors since the drug was not removed after the adsorption step. Second, the drug was not preincubated with the virus, and thus according to the model, a much smaller effect of the drug on the virus was expected than when the drug was preincubated with the virus. Indeed, a dramatically smaller effect of the drug was observed: ~2.7-fold inhibition versus 3-4 logs inhibition when the drug was preincubated with the virus. These results further support our model that ethacridine inhibits SARS-CoV-2 by mainly inactivating the viral particles (Fig. 5A-5D).

[0080] Further validation in human cells. To ensure that the antiviral effect is not restricted to the Vero E6 cells, the anti-viral effect of ethacridine was further evaluated in human cells. A human lung epithelial A549 cell line stably expressing human ACE2 (A549^ACE2) and human primary nasal epithelial (HNE) cells were used. A plaque assay in A549^ACE2 cells revealed that ethacridine-treated virus showed a dramatic decrease in infectivity when applied to A549^ACE2 cells (Fig. 6B), indicating that the effect of virus inactivation of ethacridine is not specific to Vero E6 cells. This was consistent with the suggested mode of action of ethacridine by inactivating SARS-CoV-2 particles. The cilia organelles within the nasal epithelium have been shown to strongly and specifically express the ACE2 receptor exploited by SARS-CoV-2 . To validate the antiviral effects of ethacridine in airway epithelia cultures, primary HNE cells were infected with ethacridine-treated virus and incubated with the media containing 5 pM ethacridine for 48 hours. Immunostaining with anti-N and anti-S antibodies in HNE cells showed that, in the presence of ethacridine, the proportion of infected primary nasal cells was dramatically decreased, demonstrating that ethacridine protected HNE cells from viral infection (Fig. 6A). These data show that the antiviral effect of ethacridine is cell type-independent, consistent with the main mode of action of this drug. Lastly, it was examined whether ethacridine inhibits virus reproduction in the HNE cells by the same mechanism as in Vero E6 cells. Virions were pre-incubated with the drugs and then to the HNE cells. Immediately after adsorption, the sample was washed to remove the drug. The cells were then incubated with drug-free medium. Immunostaining was conducted showing strong inhibition of the virions in the HNE cell (Fig. 6C). Therefore, our data show that ethacridine inhibits the virions in the HNE cells by the same mechanism as in the Vero E6 cells.

[0081] All patents, patent applications, and publications cited in this specification are herein incorporated by reference to the same extent as if each independent patent application, or publication was specifically and individually indicated to be incorporated by reference. The disclosed embodiments are presented for purposes of illustration and not limitation. While the invention has been described with reference to the described embodiments thereof, it will be appreciated by those of skill in the art that modifications can be made to the structure and elements of the invention without departing from the spirit and scope of the invention as a whole.

[0082] TABLE I. List of Ethacridine Derivatives: Ethacridine (PubChem ID number: 2017), Acridine, 9-amino-2-methoxy- (PubChem ID number: 18867), 7-Methoxy-l, 2,3,4- tetrahydroacridin-9-amine (PubChem ID number: 119053), 6-Ethoxy-2-methylquinoline (PubChem ID number: 81118), ACRIDINE, 9-(p-ANISIDINO)- (PubChem ID number: 43640), 2-Ethoxy-6-nitroacridin-9-amine (PubChem ID number: 30102), 4-[6-(2- Fluoroethoxy)-2-quinolinyl]benzenamine (PubChem ID number: 76023983), 6-Methoxy-2- methylquinolin-4-amine (PubChem ID number: 774820), Acridin-9-yl(4- ethoxyphenyl)amine, chloride (PubChem ID number: 2788193), 6-Ethoxy-2,4- dimethylquinoline (PubChem ID number: 221515), Acridine, 2-methoxy- (PubChem ID number: 18690), 6-Iodo-2-methoxyacridin-9-amine (PubChem ID number: 71575186), 6- Iodo-2-methoxy-N-methylacridin-9-amine (PubChem ID number: 71575185), 4-[6-(2- (18F)Fluoranylethoxy)quinolin-2-yl]aniline (PubChem ID number: 53362021), N-Hexyl-7- m ethoxy- 1,2, 3, 4-tetrahydroacridin-9-amine (PubChem ID number: 52941983), (6-Methoxy- 2-methyl-quinolin-4-yl)-p-tolyl-amine (PubChem ID number: 23724347), N-Heptyl-7- methoxy-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 10496398), 9-N-(4- Methoxyphenyl)acridine-3,6,9-triamine (PubChem ID number: 10359283), l-N-(6-Ethoxy-2- methylquinolin-4-yl)-4-N,4-N-dimethylbenzene-l,4-diamine;hydrochloride (PubChem ID number: 2790771), N-(4-Ethoxyphenyl)-2,6-dimethylquinolin-4-amine (PubChem ID number: 798218), N-(4-Ethoxyphenyl)-2,8-dimethylquinolin-4-amine (PubChem ID number: 715734), l-N,l-N-Diethyl-4-N-(2-methoxyacridin-9-yl)pentane-l,4-diamine (PubChem ID number: 408117), N-(4-Ethoxyphenyl)acridin-9-amine (PubChem ID number: 232570), 9- Acridinamine, 6-azido-2-ethoxy- (PubChem ID number: 155813), 7-Methoxy-3-acridinamine (PubChem ID number: 133838), 9-Amino-3-azido-7-methoxyacridine (PubChem ID number: 125938), 3-N-Benzyl-7-ethoxyacridine-3,9-diamine (PubChem ID number: 137653840), 7- Methoxy-N-pent-4-enyl-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 54753261), 6-Methoxy-2-phenylquinolin-4-amine (PubChem ID number: 22395288), N-(9- Amino-7-ethoxyacridin-3-yl)acetamide (PubChem ID number: 15644447), 6-Methoxy-2- phenylquinoline (PubChem ID number: 10585838), 4-[(E)-2-(6-Ethoxyquinolin-2- yl)ethenyl]-N,N-dipropylaniline (PubChem ID number: 6300604), 4-[(E)-2-(6- Ethoxyquinolin-2-yl)ethenyl]-N,N-dimethylaniline (PubChem ID number: 5836776), 3- Azido-9-((4-(diethylamino)-l-methylbutyl)amino)-7-methoxyacridine (PubChem ID number: 3037609), N-(4-Ethoxyphenyl)-2,6,8-trimethylquinolin-4-amine;hydrochloride (PubChem ID number: 2790792), 6-Ethoxy-N-(4-methoxyphenyl)-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 2790764), 4-(Quinolin-2-ylmethoxy)aniline (PubChem ID number: 2747569), l-N-(6-Ethoxy-2-methylquinolin-4-yl)-4-N,4-N-dimethylbenzene-l,4-diamine (PubChem ID number: 696596), 6-Ethoxy-N-(4-ethoxyphenyl)-2-methylquinolin-4-amine (PubChem ID number: 696591), 4-Azido-6-methoxy-2-phenyl-quinoline (PubChem ID number: 494305), 6-[2-(4-Amino-2-methyl-quinolin-6-yl)oxyethoxy]-2-methyl-quinolin-4- amine (PubChem ID number: 409679), 2-Ethoxyacridin-9-amine (PubChem ID number: 342948), 6-((9-Amino-7-ethoxy-3-acridinyl)diazenyl)-2-ethoxy-9-acridinylamine (PubChem ID number: 326830), 6-[[4-(Dimethylamino)phenyl]diazenyl]-2-ethoxyacridin-9-amine (PubChem ID number: 324793), lodorivanol (PubChem ID number: 191972), 7,8,9,10- Tetrahydro-1 l-amino-2-methoxy-6H-cyclohepta(b)quinoline (PubChem ID number: 22007), 2-[[(9-Amino-7-ethoxyacridin-3-yl)amino]methyl]cyclohexa-2,4-diene-l-thione (PubChem ID number: 137639675), 2-Methoxyacridine;dihydrochloride (PubChem ID number: 129722990), 6-Chloro-2-ethoxyacridin-9-amine (PubChem ID number: 71700026), 2-(3- Propan-2-yloxyphenyl)quinoline (PubChem ID number: 69958604), N-(2-Methoxyacridin-9- yl)-N',N'-dimethylpropane-l,3-diamine;hydrochloride (PubChem ID number: 54606094), 6- [2-(4-Amino-2-methylquinolin-6-yl)oxyethoxy]-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 54604896), 2-(Bromomethyl)-7-methoxyacridin-9-amine (PubChem ID number: 49863667), 2-Methoxy-7-methylacridin-9-amine (PubChem ID number: 49863666), 7-Ethoxy-3-N-[(2-methoxyphenyl)methyl]acridine-3,9-diamine (PubChem ID number: 44715141), 2-Methoxy-9-methylacridine (PubChem ID number: 24975174), N-(4- Pentoxyphenyl)acridin-9-amine;hydrochloride (PubChem ID number: 24196399), N-(4- Propoxyphenyl)acridin-9-amine;hydrochloride (PubChem ID number: 24196392), 4-[(2- Methylquinolin-4-yl)methoxy]aniline (PubChem ID number: 22392783), 2-Ethoxyacridine- 1,3-diamine (PubChem ID number: 21618246), N-(4-Butoxyphenyl)acridin-9- amine;hydrochloride (PubChem ID number: 21144624), 8-Ethoxyacridine-3,9-diamine (PubChem ID number: 20528088), 2-Methyl-4-[4-(benzyloxy)phenylamino]quinoline (PubChem ID number: 15681650), 2-Methoxy-6-nitroacridine (PubChem ID number: 15352298), 9-Isothiocyanato-2-methoxyacridine (PubChem ID number: 13545465), 4- Amino-6-ethoxy-2-methylquinoline (PubChem ID number: 12411653), N-(4- Hexoxyphenyl)acridin-9-amine (PubChem ID number: 10666866), 6-Ethoxy-2-[(E)-2- phenylethenyl]quinoline (PubChem ID number: 6065314), 2-Methyl-6-butoxy-4-quinolinyl azide (PubChem ID number: 3977143), 7-Ethoxy-3-N-[(4-methoxyphenyl)methyl]acridine- 3,9-diamine (PubChem ID number: 2885134), 6-Ethoxy-2-methyl-N-(3-nitrophenyl)-4- quinolinamine hydrochloride (PubChem ID number: 2790774), 6-Methoxy-N-(4- methoxyphenyl)-2-methylquinolin-4-amine (PubChem ID number: 831190), N-(4- Methoxyphenyl)-2,6-dimethylquinolin-4-amine (PubChem ID number: 698974), 6-Ethoxy- N-(2-ethoxyphenyl)-2-methylquinolin-4-amine (PubChem ID number: 696589), N-(4- Ethoxyphenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 696503), (6- Methoxy-2-methyl(4-quinolyl))phenylamine (PubChem ID number: 673739), N-(4- Methoxyphenyl)-2-methylquinolin-4-amine (PubChem ID number: 659958), 2-Ethoxy-6- iodoacridin-9-amine (PubChem ID number: 342949), 4-(2-(6-Methoxy-2- quinolinyl)ethanimidoyl)-N,N-dimethylaniline (PubChem ID number: 224870), 2-Ethoxy-l- nitroacridin-9-amine (PubChem ID number: 154400077), 2-Ethoxy-9-nitroacridin-l -amine (PubChem ID number: 154363697), 6-(4-Amino-2-methylquinolin-6-yl)oxy-2- methylquinolin-4-amine (PubChem ID number: 154247261), 7-Ethoxyacridin-3-amine (PubChem ID number: 154207255), 2-Ethoxy-9-phenylacridine (PubChem ID number: 154145368), 9-Azido-2-methoxyacridine (PubChem ID number: 154134624), 2-Ethoxy-N- ethylacridin-9-amine (PubChem ID number: 154127631), 2-Phenylmethoxyquinolin-5 -amine (PubChem ID number: 153885857), 6-Ethoxy-2-pent-l-enylquinolin-4-amine (PubChem ID number: 153802921), 6-Ethoxy-2-oct-l-enylquinolin-4-amine (PubChem ID number: 153802919), 6-Ethoxy-2-(2-phenylethenyl)quinolin-4-amine (PubChem ID number: 153798714), N-Butyl-2-ethoxyacridin-9-amine (PubChem ID number: 153798433), 7- Ethoxy-9-N-ethylacridine-3,9-diamine (PubChem ID number: 153793994), l-(2- Ethoxyacridin-9-yl)-2-phenylhydrazine (PubChem ID number: 153791944), Ethane;2-ethyl- 6-methoxyquinolin-4-amine (PubChem ID number: 153540489), 4-Amino-3,5- dimethylphenol;7-ethoxyacridine-3,9-diamine (PubChem ID number: 153328758), 2- Methoxyacridin- 10-ium (PubChem ID number: 152759311), 2,7-Dimethoxyacridin-10-ium (PubChem ID number: 152755957), 3-Azido-5-fluoro-2-methoxyacridine (PubChem ID number: 152638637), 4-(Acridin-2-yloxymethyl)-N-azidoaniline (PubChem ID number: 152623151), l-Azido-2-dodecoxyacridine (PubChem ID number: 152590579), 2- Decoxyacridine (PubChem ID number: 152448185), 2-[(6-Methoxyquinolin-2-yl)methoxy]- 4-methylaniline (PubChem ID number: 152444755), 3-Azido-2-phenoxyacridine (PubChem ID number: 152444593), 2-(l-Methoxypropan-2-yloxy)acri din-3 -amine (PubChem ID number: 152443115), 4-Amino-6-ethoxy-2-(4-fluorophenyl)quinoline-3-carbonitrile (PubChem ID number: 152382722), 4- Azido-2-methyl-6-phenoxy quinoline (PubChem ID number: 152295375), 3-Azido-2-propoxyacridine (PubChem ID number: 152197758), 1- Azido-2-methoxyacridine (PubChem ID number: 152079024), 6-Azido-2-decoxyacridin-9- amine (PubChem ID number: 151974928), 3-Azido-2-decoxyacridine (PubChem ID number: 151791607), N-Azido-2-methoxyacridin-3-amine (PubChem ID number: 151728088), 1- Azido-2-(3,7-dimethyloctoxy)acridine (PubChem ID number: 151719390), 5-Iodo-2-propan- 2-yloxyacridine (PubChem ID number: 151648329), 3-Azido-2-methoxyacridine (PubChem ID number: 151334482), 2-(2-Methylpropoxy)acridine (PubChem ID number: 151245256), l-Azido-2-propoxyacridine (PubChem ID number: 151178697), l-Azido-4-decoxyacridine (PubChem ID number: 151176678), l-Azido-2-propan-2-yloxyacridine (PubChem ID number: 151128471), 4-(6-Methoxyquinolin-2-yl)benzenecarboximidate (PubChem ID number: 151054974), 2-(3-Aminoacridin-2-yl)oxy ethanol (PubChem ID number: 150876676), l-Azido-2-ethoxyacridine (PubChem ID number: 150832756), N-(4- Azidophenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 150389194), 2- Ethenoxyacridine (PubChem ID number: 150266647), 6-Ethoxy-3-octyl-2-phenylquinoline (PubChem ID number: 150227087), 2-Methoxyacri din-3 -amine (PubChem ID number: 150218886), 3-Azido-2-ethoxyacridine (PubChem ID number: 150165088), 2-(4- Azidophenyl)-6-methoxy quinoline (PubChem ID number: 149866249), 6-Ethoxy-3-ethyl-2- propylquinoline (PubChem ID number: 149846357), 2-Phenoxyacridine (PubChem ID number: 149831594), 2-[2-(4-Methoxyphenyl)ethyl]quinoline-4,7-diamine (PubChem ID number: 149755764), (2-Fluoro-6-methoxyquinolin-4-yl)azanide (PubChem ID number: 149732600), 9-Azido-7-methoxy-l,2,3,4-tetrahydroacridine (PubChem ID number: 149639404), l-(6-Methoxyquinolin-2-yl)ethanimine (PubChem ID number: 148162689), 4- [6-[(2S)-3-Fluoro-2-methylpropoxy]quinolin-2-yl]-N,N-dimethylaniline (PubChem ID number: 146806500), 2-Methyl-4-[[4-(sulfinatoamino)phenoxy]methyl]quinoline (PubChem ID number: 145516915), Ethane;methane;N-(4-methoxyphenyl)acridin-9-amine (PubChem ID number: 144507989), 2,3-Bis(ethenyl)-N-(4-methoxyphenyl)quinolin-4-amine;ethane (PubChem ID number: 144507983), 2-[3-(2-Methylpropoxy)phenyl]quinoline (PubChem ID number: 144379335), 2-[3-(2,2-Dimethylpropoxy)phenyl]quinoline;ethane (PubChem ID number: 144379334), l-[2-(4-Aminophenyl)quinolin-6-yl]oxybutan-2-olate (PubChem ID number: 144371572), Ethane;6-methoxy-2-methyl-N-(4-methylphenyl)quinolin-4-amine (PubChem ID number: 143326841), 6-[2-[(Z)-3-(4-Amino-3-ethyl-6-methylpyridin-2- yl)prop-2-enoxy]ethoxy]-2-methylquinolin-4-amine (PubChem ID number: 143204376), N- Butyl-2-ethoxyacridin-l -amine (PubChem ID number: 142776347), 2-[8-(4- Methylphenoxy)octyl]quinolin-4-amine (PubChem ID number: 142727650), 2-[8-(4- Fluorophenoxy)octyl]quinolin-4-amine (PubChem ID number: 142727649), 2-[8-(2- Methylphenoxy)octyl]quinolin-4-amine (PubChem ID number: 142727646), 2-[8-(3 - Fluorophenoxy)octyl]quinolin-4-amine (PubChem ID number: 142727642), 1- Ethoxyacridine-3,9-diamine (PubChem ID number: 142721317), 4-(6-Butoxyquinolin-2-yl)- N-methylaniline (PubChem ID number: 142517260), N-Methyl-4-[6-(3- methylbutoxy)quinolin-2-yl]aniline (PubChem ID number: 142517099), 7-Methoxy-4- methyl-1 -nitroacridine (PubChem ID number: 142081424), 2-[(3- Phenylmethoxyphenyl)methyl]quinolin-4-amine (PubChem ID number: 141719121), 4-(6- Methoxyquinolin-2-yl)oxyaniline (PubChem ID number: 141219208), 2-Ethoxy-6- nitroacridin-9-amine;hydrochloride (PubChem ID number: 141207094), 2- Phenylmethoxyacridine (PubChem ID number: 140271931), 7-Phenylmethoxy-l, 2,3,4- tetrahydroacridine (PubChem ID number: 140271833), 2-Phenyl-6-phenylmethoxyquinoline (PubChem ID number: 140041368), 2-Methoxy-10-methylacridin-10-ium-3,6- diamine;chloride (PubChem ID number: 139844117), 2-(6,9-Diaminoacridin-2-yl)oxyethanol (PubChem ID number: 139619286), 7-Ethenoxyacridine-3,9-diamine (PubChem ID number: 139619285), 6-[[2-(Dimethylamino)phenyl]diazenyl]-2-ethoxyacridin-9-amine (PubChem ID number: 139347690), 4-[(9-Amino-7-ethoxyacridin-3-yl)diazenyl]-3,5- dimethylphenol;hydrate (PubChem ID number: 139347685), 6-[[2- (Diethylamino)phenyl]diazenyl]-2-ethoxyacridin-9-amine (PubChem ID number: 139347681), 4-[(9-Amino-7-ethoxyacridin-3-yl)diazenyl]-3,5-dimethylphenol (PubChem ID number: 139347679), 6-Ethoxy-4-ethyl-2-methylquinoline (PubChem ID number: 139326647), N-Methyl-4-(6-propoxyquinolin-2-yl)aniline (PubChem ID number: 137419005), N-Methyl-4-[6-(3-methylbut-3-enoxy)quinolin-2-yl]aniline (PubChem ID number: 137418973), 4-[6-(2,4-Dimethylpentoxy)quinolin-2-yl]-N,N-dimethylaniline (PubChem ID number: 137418931), N,N-Dimethyl-4-[6-(2-methylpentoxy)quinolin-2- yl]aniline (PubChem ID number: 137418929), 4-[6-(2-Fluoroethoxy)quinolin-2-yl]-N- propan-2-ylaniline (PubChem ID number: 137418869), N-[4-[(4- Aminophenyl)methyl]phenyl]-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 137376739), 2-Methyl-8-phenoxyquinolin-5-amine (PubChem ID number: 135373690), 13H-Quinolino[3,2-a]phenoxazine (PubChem ID number: 134346932), 4-Ethoxyacridin-9- amine (PubChem ID number: 129886186), CID 129803113 (PubChem ID number: 129803113), 7-Methoxyacridine-2,9-diamine (PubChem ID number: 129671658), 7- Methoxy-9-methylacridin-2-amine (PubChem ID number: 129650891), 2-(3- Methylbutoxy)acridin-9-amine (PubChem ID number: 129641992), 9-N-[5- (Diethylamino)pentan-2-yl]-2,4-difluoro-7-methoxyacridine-3,9-diamine (PubChem ID number: 123970648), 6-Cyclohexyloxy-2-methylquinoline (PubChem ID number: 123698682), 7-Ethoxyacridine-l,3,9-triamine (PubChem ID number: 123229432), 9-N-[3- [Benzyl(methyl)amino]propyl]-7-methoxy-9-N-methylacridine-3,9-diamine (PubChem ID number: 122662731), 3-[2-[4-(Dimethylamino)phenyl]quinolin-6-yl]oxypropyl hypofluorite (PubChem ID number: 122530231), 4-[6-(2-Methylbutoxy)quinolin-2-yl]aniline (PubChem ID number: 118655128), N,N-Diethyl-4-(6-pentan-3-yloxyquinolin-2-yl)aniline (PubChem ID number: 118655063), N-Methyl-4-(6-phenylmethoxyquinolin-2-yl)aniline (PubChem ID number: 118168564), 7-Methoxy-9-chloroacridine-3-amine (PubChem ID number:

101843626), 2-Isopropoxy-6-nitroacridine-9-amine (PubChem ID number: 101367622), 4- (2-Methoxy-7-methylacridin-9-yl)butan-l -amine (PubChem ID number: 89517933), 3-(2- Methoxy-7-methylacridin-9-yl)oxypropan-l-amine (PubChem ID number: 89517930), N'-(2- Methoxy-7-methylacridin-9-yl)propane-l,3-diamine (PubChem ID number: 89517929), 9-N- (l-Ethylpiperidin-4-yl)-7-methoxyacridine-3,9-diamine (PubChem ID number: 89182834), 9-N-[4-[Cyclopropylmethyl(ethyl)amino]butyl]-7-methoxyacridine-3,9-diamine (PubChem ID number: 89182818), N-[2-[2-(Diethylamino)ethoxy]ethyl]-2-methoxyacridin-9-amine (PubChem ID number: 89182811), N-Chloro-4-[6-(2-fluoroethoxy)quinolin-2-yl]-N- methylaniline (PubChem ID number: 88919792), CID 88813332 (PubChem ID number: 88813332), 7-Methoxyacridin-l -amine (PubChem ID number: 88458053), 4- Methoxyacridin-1 -amine (PubChem ID number: 88458052), 7-Ethoxyacridine-2,3-diamine (PubChem ID number: 88284855), Azanium;7-ethoxyacridine-3,9-diamine;hydrogen sulfate (PubChem ID number: 88078663), 2-Methoxy-6-nitroacridin-9-amine (PubChem ID number: 85784745), 2,4-Dimethyl-6-phenylmethoxyquinoline (PubChem ID number: 82580885), 2- Methyl-6-propan-2-yloxyquinoline (PubChem ID number: 82241296), (2S)-7- Phenylmethoxy-2-propyl-l,2,3,4-tetrahydroacridine (PubChem ID number: 71724390), 6- (125I)Iodanyl-2-methoxyacridin-9-amine (PubChem ID number: 71575413), 6- (125I)Iodanyl-2-m ethoxy -N-methylacridin-9-amine (PubChem ID number: 71575412), 2- Ethoxy-N-methyl-6-{(E)-[2-(methylamino)phenyl]diazenyl}acridin-9-amine (PubChem ID number: 71440922), 2-Ethoxy-N-ethyl-6-{(E)-[2-(ethylamino)phenyl]diazenyl}acridin-9- amine (PubChem ID number: 71440921), N-(3-Fluorophenyl)-2-methoxyacridin-9-amine (PubChem ID number: 71386941), N-(4-Fluorophenyl)-2-methoxyacridin-9-amine (PubChem ID number: 71386543), 6-Ethoxy-2-(4-phenylbuta-l,3-dien-l-yl)quinolin-4- amine (PubChem ID number: 71379429), 2-Quinolineethanamine, 6-methoxy- (PubChem ID number: 71149418), 2-(2-Methylquinolin-6-yl)oxyacetonitrile (PubChem ID number: 70447869), N-Benzyl-6-methoxy-2-prop-2-enylquinolin-4-amine (PubChem ID number: 70368057), Quinoline, 2-methyl-6-(2-propen-l-yloxy)- (PubChem ID number: 70351801), 2- [3-(2,2-Dimethylpropoxy)phenyl]quinoline (PubChem ID number: 69958270), 2-(3- Propoxyphenyl)quinoline (PubChem ID number: 69958205), 2-(3-Ethoxyphenyl)quinoline (PubChem ID number: 69958204), 2,4-Dimethyl-3-[(2-methylquinolin-6- yl)oxymethyl]aniline (PubChem ID number: 69830030), 4-(6-Butoxyquinolin-2-yl)-N,N- di ethylaniline (PubChem ID number: 69620497), 4-Amino-6-methoxy-2-(3- methoxyphenyl)quinoline (PubChem ID number: 69239758), Azane;2-(3-methoxyphenyl)-6- methylquinolin-4-amine (PubChem ID number: 69205301), 4-Hexyl-3-methyl-2-(2- methylpropyl)-6-phenylmethoxy quinoline (PubChem ID number: 69152728), [4-Butyl-2-(2- methylpropyl)-6-phenylmethoxyquinolin-3-yl]methanamine (PubChem ID number: 68829028), [4-Hexyl-2-(2-methylpropyl)-6-phenylmethoxyquinolin-3-yl]methanamine (PubChem ID number: 68828584), N'-[2-(3-Methoxyphenyl)quinolin-7-yl]ethanimidamide (PubChem ID number: 68545192), 6-Ethoxy-2-propylquinoline (PubChem ID number: 68402041), 4-[(E)-2-(6-Ethoxyquinolin-2-yl)ethenyl]-N,N-diethylaniline (PubChem ID number: 67931585), 2-Methyl-N-(4-phenylmethoxyphenyl)quinolin-4-amine;hydrochloride (PubChem ID number: 67698685), 4-[2-(2-Methylquinolin-4-yl)ethoxy]aniline (PubChem ID number: 67440159), 4-[(2-Methylquinolin-4-yl)methoxy]aniline;dihydrochloride (PubChem ID number: 67305537), 4-[(2-Methylquinolin-4-yl)methoxy]aniline;hydrochloride (PubChem ID number: 67304219), 2-Methyl-6-phenoxyquinolin-4-amine (PubChem ID number: 62195935), 6-Butoxy-2-(4-decylphenyl)quinoline (PubChem ID number: 59933333), 2-(4- Methylphenyl)-6-pentoxyquinoline (PubChem ID number: 59933283), 4-[(6-Fluoro-2- methylquinolin-4-yl)methoxy]aniline (PubChem ID number: 59613847), 4-[l-(2- Methylquinolin-4-yl)ethoxy]aniline (PubChem ID number: 59613805), N-[2-[2-(2- Aminophenyl)ethyl]phenyl]-2-methyl-6-phenylmethoxyquinolin-4-amine (PubChem ID number: 58807259), 2,6-Dimethyl-N-[2-[2-[2-[(2-methyl-6-phenylmethoxyquinolin-4- yl)amino]phenyl]ethyl]phenyl]quinolin-4-amine (PubChem ID number: 58807115), 4-[6-(2- Fluoroethoxy)quinolin-2-yl]-N-methylaniline (PubChem ID number: 58362623), 2-Fluoro-4- (6-methoxyquinolin-2-yl)aniline (PubChem ID number: 58362499), N-Methyl-4-[6-[2-(2- propoxyethoxy)ethoxy]quinolin-2-yl]aniline (PubChem ID number: 58362459), N,N- Dimethyl-4-[6-[2-(2-propoxyethoxy)ethoxy]quinolin-2-yl]aniline (PubChem ID number: 58362393), 2-Methyl-6-phenoxyquinoline (PubChem ID number: 57456355), 2- Ethoxyacridine (PubChem ID number: 56612660), 6-[4-(4-Amino-2-methylquinolin-6- yl)oxybutoxy]-2-methylquinolin-4-amine dihydrochloride (PubChem ID number: 54604895), 4-[2-(6-Ethoxyquinolin-2-yl)ethenyl]-N,N-diethylaniline (PubChem ID number: 54484777), 8-Chloro-7-ethoxyacridine-3,9-diamine (PubChem ID number: 54007033), 2,7- Dimethoxyacridine (PubChem ID number: 53662246), 3-(2,7-Dimethoxyacridin-9- yl)oxypropan-l -amine (PubChem ID number: 53475922), N'-(2,7-Dimethoxyacridin-9- yl)propane- 1,3 -diamine (PubChem ID number: 53475921), 4-Amino-6-methoxy-2- phenylquinoline hydrochloride (PubChem ID number: 53421251), 6-Methoxy-2-methyl-N- (4-methylphenyl)quinolin-4-amine;chloride (PubChem ID number: 53351663), 2-Propyl-6- (trifluoromethoxy)quinolin-4-amine (PubChem ID number: 52336094), 2-Phenyl-6- (trifluoromethoxy)quinolin-4-amine (PubChem ID number: 51600280), 4-(6- Methoxyquinolin-2-yl)aniline (PubChem ID number: 50917106), 3-(6-Methoxy-2- quinolyl)aniline (PubChem ID number: 49777981), 4-(6-Methoxyquinolin-2-yl)-N- methylaniline (PubChem ID number: 46931568), 6-Methoxy-2-propylquinolin-4-amine (PubChem ID number: 45599333), 6-Ethoxy-2-phenylquinolin-4-amine (PubChem ID number: 45599221), 2-Ethenyl-6-ethoxyquinoline (PubChem ID number: 44609992), 4-N- (2-Methoxyacridin-9-yl)benzene-l,4-diamine (PubChem ID number: 44337031), N-(2,5- Dimethylphenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 24151945), 7-Ethoxyacridine-3,9-diamine;hydrate (PubChem ID number: 23617571), 3-(2,3- Dimethylquinolin-6-yl)oxypropan-l -amine (PubChem ID number: 23557918), N-(4- Butylphenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 22417889), 4-[4- (Cyclohexylmethoxy)anilino]-2-methylquinolin-6-ol (PubChem ID number: 22417863), 2- (4-Pentylphenyl)-6-decyloxyquinoline (PubChem ID number: 21466810), N-(7-Methoxy- l,2,3,4-tetrahydroacridin-9-yl)hydroxylamine (PubChem ID number: 21192892), 2-Tert- butyl-6-phenylmethoxyquinoline (PubChem ID number: 20709519), 7-Ethoxyacridine-l,3- diamine (PubChem ID number: 20525499), 7-Methoxyspiro[3,4-dihydro-lH-acridine-2,l'- cyclohexane]-9-amine (PubChem ID number: 20029212), 6-Ethoxy-2-methylquinolin-l-ium (PubChem ID number: 19816694), 2-Ethyl-6-propan-2-yloxy quinoline (PubChem ID number: 19389921), 2-Ethyl-6-(2-fluoroethoxy)quinoline (PubChem ID number: 19389897), 7-Methoxy-4-methyl-l-nitroacridin-9-amine (PubChem ID number: 18505082), 7-Methoxy-

1-nitroacridin-9-amine (PubChem ID number: 18505073), 2-(3-Methoxyphenyl)-4,6- quinolinediamine (PubChem ID number: 18439888), 3-N-(6-Methoxy-2-methylquinolin-4- yl)benzene-l,3-diamine (PubChem ID number: 17752485), 6-Ethoxy-2-methyl-N-(3- nitrophenyl)quinolin-4-amine;chloride (PubChem ID number: 16461089), N-(9-Acetamido- 7-ethoxyacridin-3-yl)acetamide (PubChem ID number: 15644448), 7-Methoxy-l, 2,3,4- tetrahydroacridin-9-amine;hydrochloride (PubChem ID number: 15300703), 4-(l-Quinolin-

2-ylethoxy)aniline (PubChem ID number: 14127609), 9-Hydrazinyl-2-methoxyacridine (PubChem ID number: 13914008), 2-Ethoxyacridine-3,6-diamine (PubChem ID number: 13823374), 2-Methyl-4-(quinolin-2-ylmethoxy)aniline (PubChem ID number: 13688381), 6- Ethoxyacridine-3,9-diamine (PubChem ID number: 13072102), 6-Azido-9-chl oro-2 - methoxyacridine (PubChem ID number: 12703086), 2-Methoxyacridin-l -amine (PubChem ID number: 12643654), 9-N-(4-Methoxyphenyl)acridine-3,9-diamine;hydrochloride (PubChem ID number: 12370526), 9-N-(4-Methoxyphenyl)acridine-3,9-diamine (PubChem ID number: 12370525), 9-Acridinamine, 2-methoxy-N-methyl- (PubChem ID number: 12296137), 7-Ethoxyacridine-3,9-diamine hydrochloride (PubChem ID number: 12228017), 6-Methoxy-N-[4-[(E)-N-methoxy-C-methylcarbonimidoyl]phenyl]-2-phenylquinolin-4- amine (PubChem ID number: 11610967), (NE)-N-[l-[4-[(6-methoxy-2-phenylquinolin-4- yl)amino]phenyl]ethylidene]hydroxylamine (PubChem ID number: 11589053), 6- (Benzyloxy)-2-methoxyquinoline (PubChem ID number: 11219306), l-Fluoro-2- methoxyacridin-9-amine (PubChem ID number: 11218719), 6-Methoxy-3-methyl-2- phenylquinoline (PubChem ID number: 10901024), 2-Methyl-4-[4- butoxyphenylamino]quinoline (PubChem ID number: 10380453), 7-Ethoxyacridin-10-ium- 3,9-diamine (PubChem ID number: 5257065), 7-Methoxyacridine-3,9-diamine (PubChem ID number: 4142514), 2,6,8-Trimethyl-N-(4-phenylmethoxyphenyl)quinolin-4- amine;hydrochloride (PubChem ID number: 2790798), 6-Ethoxy-N-(4-ethoxyphenyl)-2- methylquinolin-4-amine;hydrochloride (PubChem ID number: 2790766), 6-Ethoxy-N-(3- methoxyphenyl)-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 2790763), 6-Ethoxy-N-(2-methoxyphenyl)-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 2790762), 4-[(6-Ethoxy-2-methylquinolin-4-yl)amino]phenol;hydrochloride (PubChem ID number: 2790761), 6-Ethoxy-N-(4-iodophenyl)-2-methylquinolin-4- amine;hydrochloride (PubChem ID number: 2790758), N-(4-Ethoxyphenyl)-6-methoxy-2- methylquinolin-4-amine;hydrochloride (PubChem ID number: 2790591), N-(2- Ethoxyphenyl)-6-methoxy-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 2790590), N-(4-Butoxyphenyl)-6-methoxy-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 2790589), N-(4-Methoxyphenyl)-2,6-dimethylquinolin-4- amine;hydrochloride (PubChem ID number: 2789800), 9-N-(3-Aminopropyl)-7- ethoxyacridine-3,9-diamine (PubChem ID number: 2786625), 2-Ethoxy-6-amino-9- chloroacridine (PubChem ID number: 2786617), N-[4-(Benzyloxy)phenyl]-2,6,8- trimethylquinolin-4-amine (PubChem ID number: 1566096), N-(4-Butoxyphenyl)-6- methoxy-2-methylquinolin-4-amine (PubChem ID number: 1564588), N-(4-Iodophenyl)-6- methoxy-2-methylquinolin-4-amine (PubChem ID number: 1186900), N-(4- Methoxyphenyl)-2,6,8-trimethylquinolin-4-amine (PubChem ID number: 827733), 6-Ethoxy- 2-methyl-N-(3-nitrophenyl)quinolin-4-amine (PubChem ID number: 808460), N-(4- Fluorophenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 798853), 6- Methoxy-2-methyl-N-(4-methylphenyl)quinolin-4-amine (PubChem ID number: 773472), N- (4-Ethoxyphenyl)-2,6,8-trimethylquinolin-4-amine (PubChem ID number: 696649), 6- Ethoxy-N-(4-methoxyphenyl)-2-methylquinolin-4-amine (PubChem ID number: 696588), 6- Ethoxy-N-(3-methoxyphenyl)-2-methylquinolin-4-amine (PubChem ID number: 696587), 6- Ethoxy-N-(2-methoxyphenyl)-2-methylquinolin-4-amine (PubChem ID number: 696585), N- (2-Ethoxyphenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 696501), 7- Methoxy- 1,3 -dinitroacridine (PubChem ID number: 627023), (6-Butoxy-2-methyl-4- quinolyl)hydrazine (PubChem ID number: 493233), (6-Methoxy-2-phenyl-4- quinolyl)hydrazine (PubChem ID number: 460144), 4-Quinolinamine, 6,6'-[l ,4- butanediylbis(oxy)]bis[2-methyl- (PubChem ID number: 409677), 4-[2-(6-Ethoxyquinolin-2- yl)ethenyl]-N,N-dimethylaniline (PubChem ID number: 291340), N-[[4- (Diethylamino)phenyl]methyl]-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 224872), 6-Ethoxy-2-(2-phenylethenyl)quinoline (PubChem ID number: 272292), 4-[2-(6- Ethoxyquinolin-2-yl)ethenyl]-N,N-dipropylaniline (PubChem ID number: 289688), N-(2- Methoxyacridin-9-yl)-N',N'-dimethylpropane-l,3-diamine (PubChem ID number: 419023), N-(4-Propoxyphenyl)acridin-9-amine (PubChem ID number: 427736), N-(4- Butoxyphenyl)acridin-9-amine (PubChem ID number: 427737), N-(4-Pentoxyphenyl)acridin- 9-amine (PubChem ID number: 427747), 2-Methoxy-9-octadecylaminoacridine (PubChem ID number: 459790), 6-Ethoxy-4-hydrazinyl-2-methylquinoline (PubChem ID number: 472393), N-(4-Ethoxyphenyl)-7-methyl-2,3-dihydro-lH-cyclopenta[b]quinolin-9-amine (PubChem ID number: 730143), N-(4-Ethoxyphenyl)-2-methylquinolin-4-amine (PubChem ID number: 798205), 6-Methoxy-2-methyl-N-(2-methylphenyl)quinolin-4-amine (PubChem ID number: 798240), 6-Methoxy-2-methyl-N-(3-methylphenyl)quinolin-4-amine (PubChem ID number: 798243), N-(4-Ethoxyphenyl)-8-methoxy-2-methylquinolin-4-amine (PubChem ID number: 798256), 6-Ethoxy-2-methyl-N-[3-(trifluoromethyl)phenyl]quinolin-4-amine (PubChem ID number: 808124), N-(3,4-Dimethylphenyl)-6-methoxy-2-methylquinolin-4- amine (PubChem ID number: 825570), 4-N-(4-Methoxyphenyl)-2,8-dimethylquinoline-4,5- diamine (PubChem ID number: 828013), 6-Ethoxy-N-(4-iodophenyl)-2-methylquinolin-4- amine (PubChem ID number: 1187200), 4-[(6-Ethoxy-2-methyl-4-quinolyl)amino]phenol (PubChem ID number: 1187201), N-(4-Ethoxyphenyl)-6-methoxy-2-methylquinolin-l-ium- 4-amine (PubChem ID number: 1390365), N-(4-Butoxyphenyl)-6-methoxy-2- methylquinolin-l-ium-4-amine (PubChem ID number: 1564587), 2,6,8-Trimethyl-N-(4- phenylmethoxyphenyl)quinolin-l-ium-4-amine (PubChem ID number: 1566095), 7 -Ethoxy - 9-methoxyacri din-3 -amine (PubChem ID number: 2786619), N-(4-Ethoxyphenyl)-2,8- dimethylquinolin-4-amine;hydrochloride (PubChem ID number: 2790115), 6-Ethoxy-N-(2- ethoxyphenyl)-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 2790765), 6- Ethoxy-2-methyl-N-[3-(trifluoromethyl)phenyl]quinolin-4-amine;hydrochloride (PubChem ID number: 2790770), N-(4-Iodophenyl)-6-methoxy-2-methylquinolin-4- amine;hydrochloride (PubChem ID number: 2916292), 6-Methoxy-2-methyl-N-(2- phenylethyl)quinolin-4-amine (PubChem ID number: 3313352), 2,6-Dimethyl-N-(4- phenoxyphenyl)quinolin-4-amine (PubChem ID number: 3367974), Acridin-9-yl-(4- octyloxy-phenyl)-amine (PubChem ID number: 3377973), N-[4-(2- Phenoxyethoxy)phenyl]acridin-l-amine (PubChem ID number: 3584769), 7-Ethoxy-N~3 — [(E)-(4-methoxyphenyl)methylidene]acridine-3,9-diamine (PubChem ID number: 3757316), N-(4-Methoxyphenyl)-2-methylacridin-9-amine (PubChem ID number: 4010871), 4-[2-(6- Ethoxy- 1 -methylquinolin- 1-ium -2 -yl)ethenyl]-N,N-di methyl aniline (PubChem ID number: 4088723), N-(4-Ethoxyphenyl)acridin-10-ium-9-amine (PubChem ID number: 4241174), 2- Ethoxy-N-methyl-6-nitroacridin-9-amine (PubChem ID number: 4315320), N-(4- Ethoxyphenyl)-2,8-dimethylquinolin-l-ium-4-amine (PubChem ID number: 4399401), 6-[2- (4-Amino-2-methylquinolin-6-yl)oxyethoxy]-2-methylquinolin-4-amine;chloride (PubChem ID number: 5351703), (6-Butoxy-2-methylquinolin-4-yl)imino-iminoazanium (PubChem ID number: 6334152), Imino-(6-methoxy-2-phenylquinolin-4-yl)iminoazanium (PubChem ID number: 6334163), 6-Methoxy-2-methylquinolin-l-ium-4-amine (PubChem ID number: 6941809), 2-Ethoxy-6-nitroacridin-10-ium-9-amine (PubChem ID number: 7061590), 2- Ethoxy-N-methyl-6-nitroacridin-10-ium-9-amine (PubChem ID number: 7065217), 2- Methoxyacridin-10-ium-9-amine (PubChem ID number: 7224669), 7-Ethoxy-3-N-[(4- methoxyphenyl)methyl]acridin-10-ium-3,9-diamine (PubChem ID number: 7376128), N,7- Dimethoxy-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 9859934), N-[4- (Cyclohexylmethoxy)phenyl]-2-methylquinolin-4-amine (PubChem ID number: 10427748),

2-[(6-Amino-2-ethoxyacridin-9-yl)amino]ethanol (PubChem ID number: 10661722), 7- Ethoxy-9-N-propylacridine-3,9-diamine (PubChem ID number: 10685301), 2-Ethoxy-6- fluoroacridin-9-amine (PubChem ID number: 10706218), 9-Amino-7-ethoxyacridine-3- diazonium;tetrafluoroborate (PubChem ID number: 10736695), 9-Amino-7-ethoxyacridine-

3-diazonium (PubChem ID number: 10736696), l,2,4-Trifluoro-7-methoxy-N-(4- methoxyphenyl)acri din-3 -amine (PubChem ID number: 11101045), 7-Ethoxyacridine-3,4,9- triamine (PubChem ID number: 12023330), 9-Ethoxy-2-methoxyacridine (PubChem ID number: 12424199), 2-Methoxy-9-propoxyacridine (PubChem ID number: 12424200), 9- Butoxy-2-methoxyacridine (PubChem ID number: 12424201), 2-Methoxy-9-pentoxyacridine (PubChem ID number: 12424202), 9-Hexoxy-2-methoxyacridine (PubChem ID number: 12424203), 7-Ethoxy-4-iodoacridine-3,9-diamine (PubChem ID number: 12624269), 6- Methoxy-2-methylquinolin-5-amine (PubChem ID number: 13900741), N-(4-Iodophenyl)-6- methoxy-2-methylquinolin-4-amine;chloride (PubChem ID number: 16460993), N-(4- Butoxyphenyl)-6-methoxy-2-methylquinolin-4-amine;chloride (PubChem ID number: 16460996), N-(2-Ethoxyphenyl)-6-methoxy-2-methylquinolin-4-amine;chloride (PubChem ID number: 16460997), N-(4-Ethoxyphenyl)-6-methoxy-2-methylquinolin-4-amine;chloride (PubChem ID number: 16460998), 6-Ethoxy-N-(4-iodophenyl)-2-methylquinolin-4- amine; chloride (PubChem ID number: 16461074), 6-Ethoxy-N-(2-methoxyphenyl)-2- methylquinolin-4-amine;chloride (PubChem ID number: 16461076), 6-Ethoxy-N-(3- methoxyphenyl)-2-methylquinolin-4-amine;chloride (PubChem ID number: 16461077), 6- Ethoxy-N-(4-methoxyphenyl)-2-methylquinolin-4-amine;chloride (PubChem ID number: 16461078), 6-Ethoxy-N-(2-ethoxyphenyl)-2-methylquinolin-4-amine;chloride (PubChem ID number: 16461079), 6-Ethoxy-N-(4-ethoxyphenyl)-2-methylquinolin-4-amine;chloride (PubChem ID number: 16461080), 6-Ethoxy-2-methyl-N-[3- (trifluoromethyl)phenyl]quinolin-4-amine;chloride (PubChem ID number: 16461084), 1-N- (6-Ethoxy-2-methylquinolin-4-yl)-4-N,4-N-dimethylbenzene-l,4-diamine;chloride (PubChem ID number: 16461086), N-(4-Ethoxyphenyl)-2,6,8-trimethylquinolin-4- amine; chloride (PubChem ID number: 16461102), 2,6,8-Trimethyl-N-(4- phenylmethoxyphenyl)quinolin-4-amine;chloride (PubChem ID number: 16461108), N-(4- Ethoxyphenyl)acridin-9-amine;chloride (PubChem ID number: 16461272), N-(4- Methoxyphenyl)-2,6-dimethylquinolin-4-amine;chloride (PubChem ID number: 16461386), 2-Methyl-4-(quinolin-2-yloxy)aniline (PubChem ID number: 16777519), 4-N-(6-Methoxy-2- methylquinolin-4-yl)benzene-l,4-diamine (PubChem ID number: 17752247), 7- Ethoxyacridine-3,9-diamine;chloride (PubChem ID number: 20489514), 2-Ethoxyacridine- 1,6,9-triamine (PubChem ID number: 20549216), 2-Methoxy-N-prop-2-enylacridin-9-amine (PubChem ID number: 21671954), N-(2-Ethylphenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 23738749), 6-N,6-N-Diethyl-9-(3-methoxyphenyl)acridine-3,6- diamine (PubChem ID number: 23758781), 6-Ethoxy-N-(2-ethylphenyl)-2-methylquinolin-4- amine (PubChem ID number: 23761503), N-(3,4-Dimethylphenyl)-6-ethoxy-2- methylquinolin-4-amine (PubChem ID number: 23798303), 6-Ethoxy-2-methyl-N- phenylquinolin-4-amine (PubChem ID number: 23827556), 6-Ethoxy-2-methyl-N-(2- methylphenyl)quinolin-4-amine (PubChem ID number: 23878459), 6-Ethoxy-2-methyl-N- naphthalen-l-ylquinolin-4-amine (PubChem ID number: 23904673), N-(2,3- Dimethylphenyl)-6-ethoxy-2-methylquinolin-4-amine (PubChem ID number: 23969247), 3- (6-Ethoxyquinolin-2-yl)aniline (PubChem ID number: 23992341), N-(2,4-Dimethylphenyl)- 6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 24049508), N-(2,4- Dimethylphenyl)-6-ethoxy-2-methylquinolin-4-amine (PubChem ID number: 24070979), 6- Ethoxy-2-methyl-N-(3-methylphenyl)quinolin-4-amine (PubChem ID number: 24106403), 6- Ethoxy-2-methyl-N-(4-methylphenyl)quinolin-4-amine (PubChem ID number: 24132721), 6- Methoxy-2-methyl-3-prop-2-enylquinolin-4-amine (PubChem ID number: 24155530), 4- [(Z)-2-(6-Ethoxyquinolin-2-yl)ethenyl]-N,N-dipropylaniline (PubChem ID number: 40507286), 4-(2-Methylquinolin-4-yl)oxyaniline (PubChem ID number: 43525444), 2- Methyl-4-(2-methylquinolin-4-yl)oxyaniline (PubChem ID number: 43525448), 6-Methoxy- 2-methyl-N-(3-phenylpropyl)quinolin-4-amine (PubChem ID number: 44533064), 6-(6- Phenylhexoxy)quinolin-4-amine (PubChem ID number: 44533185), N-(4- Ethoxyphenyl)acridin-10-ium-9-amine;chloride (PubChem ID number: 44656379), 2,6,8- Trimethyl-N-(4-phenylmethoxyphenyl)quinolin-l-ium-4-amine;chloride (PubChem ID number: 44658661), N-(4-Ethoxyphenyl)-6-methoxy-2-methylquinolin-l-ium-4- amine; chloride (PubChem ID number: 44659367), N-(4-Butoxyphenyl)-6-methoxy-2- methylquinolin-l-ium-4-amine;chloride (PubChem ID number: 44660118), 6-Methoxy-N-(4- methoxyphenyl)-2-(l,l,2,2,2-pentafluoroethyl)-3-(trifluoromethyl)quinolin-4-amine (PubChem ID number: 44825174), 2-(4-Methoxyphenyl)quinolin-7-amine (PubChem ID number: 45073742), 6-Ethoxy-N-(2-fluorophenyl)-2-methylquinolin-4-amine (PubChem ID number: 50739366), 6-Ethoxy-N-(3-fluorophenyl)-2-methylquinolin-4-amine (PubChem ID number: 50739367), 6-Ethoxy-N-(4-fluorophenyl)-2-methylquinolin-4-amine (PubChem ID number: 50739368), N-(2,5-Dimethylphenyl)-6-ethoxy-2-methylquinolin-4-amine (PubChem ID number: 52107485), N-(3,5-Dimethylphenyl)-6-ethoxy-2-methylquinolin-4-amine (PubChem ID number: 52107487), N-(4-Tert-butylphenyl)-6-ethoxy-2-methylquinolin-4- amine (PubChem ID number: 52107489), N-(2,4-Difluorophenyl)-6-ethoxy-2- methylquinolin-4-amine (PubChem ID number: 52107502), 6-Ethoxy-2-methyl-N-(4-propan- 2-ylphenyl)quinolin-4-amine (PubChem ID number: 52107516), N-(4-Butylphenyl)-6- ethoxy-2-methylquinolin-4-amine (PubChem ID number: 52107518), N-[4-[(6-Ethoxy-2- methylquinolin-4-yl)amino]phenyl]acetamide (PubChem ID number: 52107614), N'-(6- Ethoxy-2-methylquinolin-4-yl)-N,N-diethyl-N'-phenylethane- 1 ,2-diamine (PubChem ID number: 52232185), l-N-(6-Ethoxy-2-methylquinolin-4-yl)-4-N,4-N-di ethylbenzene- 1,4- diamine (PubChem ID number: 52421984), N-Ethyl-7-methoxy-l,2,3,4-tetrahydroacridin-9- amine (PubChem ID number: 52940842), 7-Methoxy-N-pentyl-l,2,3,4-tetrahydroacridin-9- amine (PubChem ID number: 52945624), 7-Methoxy-N-propyl-l,2,3,4-tetrahydroacridin-9- amine (PubChem ID number: 52945680), N-Butyl-7-methoxy-l,2,3,4-tetrahydroacridin-9- amine (PubChem ID number: 52948055), 2-Ethyl-6-(2,2,2-trifluoroethoxy)quinolin-4-amine (PubChem ID number: 55045262), 6-Ethoxy-2-(trifluoromethyl)quinolin-4-amine (PubChem ID number: 55045311), 6-Ethoxy-2-propan-2-ylquinolin-4-amine (PubChem ID number: 55045358), 6-Ethoxy-N-methyl-2-propylquinolin-4-amine (PubChem ID number: 55045359), 7-Ethoxy-N-methyl-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 55045360), 2-Ethyl-6-(trifluoromethoxy)quinolin-4-amine (PubChem ID number: 55045363), 3-Ethyl-2-methyl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 55045508), 7-Propan-2-yloxy-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 55045509), 2-Ethyl-N-methyl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 55045510), 6-(Difluoromethoxy)-2-propan-2-ylquinolin-4-amine (PubChem ID number: 55045845), 2-Tert-butyl-6-methoxyquinolin-4-amine (PubChem ID number: 55045942), 7- Methoxy-N-methyl-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 55045991), 6- Propoxy-2-propylquinolin-4-amine (PubChem ID number: 55059976), 7 -Propoxy- 1,2, 3, 4- tetrahydroacridin-9-amine (PubChem ID number: 55060023), N-Ethyl-2-methyl-6- propoxyquinolin-4-amine (PubChem ID number: 55060024), 2-(Difluoromethyl)-6- ethoxyquinolin-4-amine (PubChem ID number: 55127765), 6-Methoxy-8-methyl-2- propylquinolin-4-amine (PubChem ID number: 55129773), 6-Ethoxy-2-methyl-3-propan-2- ylquinolin-4-amine (PubChem ID number: 55130498), 2 -Methyl-3 -propan-2 -yl-6- propoxyquinolin-4-amine (PubChem ID number: 55131461), 6-Ethoxy-N,3-diethyl-2- methylquinolin-4-amine (PubChem ID number: 55194424), 6-Ethoxy-N-ethyl-2-propan-2- ylquinolin-4-amine (PubChem ID number: 55194425), N-Methyl-2-propan-2-yl-6-propan-2- yloxyquinolin-4-amine (PubChem ID number: 55195773), 6-Methoxy-2,8-dimethylquinolin- 4-amine (PubChem ID number: 55208769), N-Ethyl-2-methyl-6-propan-2-yloxyquinolin-4- amine (PubChem ID number: 55210600), 6-Ethoxy-2-ethyl-3-methylquinolin-4-amine (PubChem ID number: 55220799), (6-Propoxy-2-propylquinolin-4-yl)hydrazine (PubChem ID number: 55221089), 2-Ethyl-3-methyl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 55221896), N-(9-Amino-7-ethoxyacridin-3-yl)-2-phenylacetamide (PubChem ID number: 56695833), 6-Ethoxy-2-methyl-N-phenylquinolin-4-amine;hydrochloride (PubChem ID number: 56728837), 6-Ethoxy-2-methyl-N-(2-methylphenyl)quinolin-4- amine;hydrochloride (PubChem ID number: 56728838), 6-Ethoxy-2-methyl-N-(3- methylphenyl)quinolin-4-amine;hydrochloride (PubChem ID number: 56728839), 6-Ethoxy- 2-methyl-N-(4-methylphenyl)quinolin-4-amine;hydrochloride (PubChem ID number: 56728840), N-(2,3-Dimethylphenyl)-6-ethoxy-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 56728841), N-(2,4-Dimethylphenyl)-6-ethoxy-2-methylquinolin-4- amine;hydrochloride (PubChem ID number: 56728842), N-(2,5-Dimethylphenyl)-6-ethoxy- 2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 56728843), N-(3,4- Dimethylphenyl)-6-ethoxy-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 56728844), N-(3,5-Dimethylphenyl)-6-ethoxy-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 56728845), N-(4-Tert-butylphenyl)-6-ethoxy-2-methylquinolin-4- amine;hydrochloride (PubChem ID number: 56728846), N-(4-Butan-2-ylphenyl)-6-ethoxy-2- methylquinolin-4-amine;hydrochloride (PubChem ID number: 56728847), N-(4-Butan-2- ylphenyl)-6-ethoxy-2-methylquinolin-4-amine (PubChem ID number: 56728848), 6-Ethoxy- N-(3-fluorophenyl)-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 56728853), N-(2,4-Difluorophenyl)-6-ethoxy-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 56728854), 6-Ethoxy-N-(2-fluorophenyl)-2-methylquinolin-4- amine;hydrochloride (PubChem ID number: 56728858), l-N-(6-Ethoxy-2-methylquinolin-4- yl)-4-N,4-N-di ethylbenzene- l,4-diamine;hydrochloride (PubChem ID number: 56728859), 6- Ethoxy-2-methyl-N-(4-propan-2-ylphenyl)quinolin-4-amine;hydrochloride (PubChem ID number: 56728863), N-(4-Butylphenyl)-6-ethoxy-2-methylquinolin-4-amine;hydrochloride (PubChem ID number: 56728864), N-[4-[(6-Ethoxy-2-methylquinolin-4- yl)amino]phenyl]acetamide;hydrochloride (PubChem ID number: 56728938), 3-Hexyl-6- methoxy-2-methylquinolin-4-amine (PubChem ID number: 57359667), 6-Methoxy-N,2- dimethylquinolin-4-amine (PubChem ID number: 60645506), 6-Phenylmethoxyquinolin-4- amine (PubChem ID number: 62192065), 7-Phenoxy-2,3-dihydro-lH-cyclopenta[b]quinolin- 9-amine (PubChem ID number: 62195934), 2-Ethyl-6-phenoxyquinolin-4-amine (PubChem ID number: 62196105), 2,3-Dimethyl-6-phenoxyquinolin-4-amine (PubChem ID number: 62196106), 6-(Difluoromethoxy)-2-phenylquinolin-4-amine (PubChem ID number: 62196273), 6-(Difluoromethoxy)-2-methylquinolin-4-amine (PubChem ID number: 62196274), 6-(Difluoromethoxy)-3-ethyl-2-methylquinolin-4-amine (PubChem ID number: 62196436), 6-(Difluoromethoxy)-2-propylquinolin-4-amine (PubChem ID number: 62196437), 6-Methoxy-2-(trifluoromethyl)quinolin-4-amine (PubChem ID number: 62196439), 6-(Difluoromethoxy)-2-ethylquinolin-4-amine (PubChem ID number:

62196599), 7-(Difluoromethoxy)-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 62196600), 3-Ethyl-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 62196601), 2-Ethyl-6-m ethoxy quinolin-4-amine (PubChem ID number: 62196602), 6- (Difluoromethoxy)-2,3-dimethylquinolin-4-amine (PubChem ID number: 62196769), 6- Methoxy-2-propan-2-ylquinolin-4-amine (PubChem ID number: 62196772), 6-Methoxy-2,3- dimethylquinolin-4-amine (PubChem ID number: 62196773), 7-Propan-2-yloxy-2,3-dihydro- lH-cyclopenta[b]quinolin-9-amine (PubChem ID number: 62196932), 6-Methoxy-N-methyl- 2-phenylquinolin-4-amine (PubChem ID number: 62196941), 2-Phenyl-6-propan-2- yloxyquinolin-4-amine (PubChem ID number: 62197085), 2-Methyl-6-propan-2- yloxyquinolin-4-amine (PubChem ID number: 62197086), 6-Propan-2-yloxy-2- (trifluoromethyl)quinolin-4-amine (PubChem ID number: 62197087), 6-Propan-2-yloxy-2- propylquinolin-4-amine (PubChem ID number: 62197245), 2-Tert-butyl-6-propan-2- yloxyquinolin-4-amine (PubChem ID number: 62197246), 6-Methoxy-N-methyl-2- propylquinolin-4-amine (PubChem ID number: 62197255), 2-Ethyl-6-propan-2- yloxyquinolin-4-amine (PubChem ID number: 62197408), 2 -Propan-2 -yl-6-propan-2- yloxyquinolin-4-amine (PubChem ID number: 62197409), 2-Ethyl-6-methoxy-N- methylquinolin-4-amine (PubChem ID number: 62197419), 2,3-Dimethyl-6-propan-2- yloxyquinolin-4-amine (PubChem ID number: 62197562), N,2-Dimethyl-6-propan-2- yloxyquinolin-4-amine (PubChem ID number: 62197564), 2-Methyl-6-(4- methylphenoxy)quinolin-4-amine (PubChem ID number: 62197727), N,2,3-Trimethyl-6- propan-2-yloxyquinolin-4-amine (PubChem ID number: 62197878), 6-Ethoxy-3-ethyl-2- methylquinolin-4-amine (PubChem ID number: 62201461), 6-Ethoxy-2-propylquinolin-4- amine (PubChem ID number: 62201462), 2-Tert-butyl-6-ethoxyquinolin-4-amine (PubChem ID number: 62201463), 6-Ethoxy-2-ethylquinolin-4-amine (PubChem ID number: 62201464), 7-Ethoxy-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 62201630), 6-Ethoxy-2,3-dimethylquinolin-4-amine (PubChem ID number: 62201631), 6-Ethoxy-N,2- dimethylquinolin-4-amine (PubChem ID number: 62201818), 6-Ethoxy-N-ethyl-2- methylquinolin-4-amine (PubChem ID number: 62201999), 6-Ethoxy-2-methyl-N- propylquinolin-4-amine (PubChem ID number: 62202000), 6-Ethoxy-N-methyl-2- (trifluoromethyl)quinolin-4-amine (PubChem ID number: 62202001), 6-Ethoxy-3-ethyl-N,2- dimethylquinolin-4-amine (PubChem ID number: 62202181), 6-Ethoxy-2-ethyl-N- methylquinolin-4-amine (PubChem ID number: 62202353), 6-Ethoxy-N,2-diethylquinolin-4- amine (PubChem ID number: 62202354), 6-Ethoxy-N-methyl-2-propan-2-ylquinolin-4- amine (PubChem ID number: 62202355), 8-Ethoxy-2-phenylquinolin-4-amine (PubChem ID number: 62202359), 2-Methyl-6-(2,2,2-trifluoroethoxy)quinolin-4-amine (PubChem ID number: 62202529), 6-(2,2,2-Trifluoroethoxy)-2-(trifluoromethyl)quinolin-4-amine (PubChem ID number: 62202530), 3-Ethyl-2-methyl-6-(2,2,2-trifluoroethoxy)quinolin-4- amine (PubChem ID number: 62202531), 6-Ethoxy-N,2,3-trimethylquinolin-4-amine (PubChem ID number: 62202533), 6-Ethoxy-N-ethyl-2,3-dimethylquinolin-4-amine (PubChem ID number: 62202534), 2-Propyl-6-(2,2,2-trifluoroethoxy)quinolin-4-amine (PubChem ID number: 62202716), 2-Tert-butyl-6-(2,2,2-trifluoroethoxy)quinolin-4-amine (PubChem ID number: 62202717), 2-Propan-2-yl-6-(2,2,2-trifluoroethoxy)quinolin-4-amine (PubChem ID number: 62202885), 7-(2,2,2-Trifluoroethoxy)-l,2,3,4-tetrahydroacridin-9- amine (PubChem ID number: 62202886), 2,3-Dimethyl-6-(2,2,2-trifluoroethoxy)quinolin-4- amine (PubChem ID number: 62202887), N,2-Dimethyl-6-(2,2,2-trifluoroethoxy)quinolin-4- amine (PubChem ID number: 62203062), 2-Ethyl-N-methyl-6-(2,2,2- trifluoroethoxy)quinolin-4-amine (PubChem ID number: 62203229), N,2,3-Trimethyl-6- (2,2,2-trifluoroethoxy)quinolin-4-amine (PubChem ID number: 62203230), 7- (Trifluoromethoxy)-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 62203248), 7- Ethoxy-2, 3-dihydro-lH-cyclopenta[b]quinolin-9-amine (PubChem ID number: 62203930), 2-Methyl-6-phenylmethoxyquinolin-4-amine (PubChem ID number: 62204128), 2-Ethyl-6- phenylmethoxyquinolin-4-amine (PubChem ID number: 62204129), 2,3-Dimethyl-6- phenylmethoxyquinolin-4-amine (PubChem ID number: 62204130), (6-Ethoxy-2- ethylquinolin-4-yl)hydrazine (PubChem ID number: 62250207), (6-Ethoxy-2-propan-2- ylquinolin-4-yl)hydrazine (PubChem ID number: 62250208), (6-Ethoxy-2-propylquinolin-4- yl)hydrazine (PubChem ID number: 62250209), (7-Ethoxy-l,2,3,4-tetrahydroacridin-9- yl)hydrazine (PubChem ID number: 62250394), (6-Ethoxy-2,3-dimethylquinolin-4- yl)hydrazine (PubChem ID number: 62250395), (6-Ethoxy-3-ethyl-2-methylquinolin-4- yl)hydrazine (PubChem ID number: 62250580), (2-Methyl-6-phenoxyquinolin-4- yl)hydrazine (PubChem ID number: 62250615), (2-Methyl-6-phenylmethoxyquinolin-4- yl)hydrazine (PubChem ID number: 62250786), (2-Ethyl-6-propan-2-yloxyquinolin-4- yl)hydrazine (PubChem ID number: 62251900), (6-Propan-2-yloxy-2-propylquinolin-4- yl)hydrazine (PubChem ID number: 62252080), (7-Propan-2-yloxy-l, 2,3,4- tetrahydroacridin-9-yl)hydrazine (PubChem ID number: 62252081), 2-(Methoxymethyl)-6- propan-2-yloxyquinolin-4-amine (PubChem ID number: 62318610), 2-(Methoxymethyl)-6- phenoxyquinolin-4-amine (PubChem ID number: 62318979), 6-Ethoxy-2- (methoxymethyl)quinolin-4-amine (PubChem ID number: 62319159), 6-Methoxy-2- (methoxymethyl)quinolin-4-amine (PubChem ID number: 62320631), 2,3-Dimethyl-6- propoxyquinolin-4-amine (PubChem ID number: 62326967), N,2-Dimethyl-6- propoxyquinolin-4-amine (PubChem ID number: 62327140), N-Methyl-6-propoxy-2- (trifluoromethyl)quinolin-4-amine (PubChem ID number: 62327141), 2-Ethyl-N-methyl-6- propoxyquinolin-4-amine (PubChem ID number: 62327314), N,2,3-Trimethyl-6- propoxyquinolin-4-amine (PubChem ID number: 62327315), (2-Ethyl-6-propoxyquinolin-4- yl)hydrazine (PubChem ID number: 62327494), (2-Propan-2-yl-6-propoxyquinolin-4- yl)hydrazine (PubChem ID number: 62327667), (2,3-Dimethyl-6-propoxyquinolin-4- yl)hydrazine (PubChem ID number: 62327668), (2-Methyl-6-propoxyquinolin-4- yl)hydrazine (PubChem ID number: 62327830), (3-Ethyl-2-methyl-6-propoxyquinolin-4- yl)hydrazine (PubChem ID number: 62328006), 2-(Methoxymethyl)-6-propoxyquinolin-4- amine (PubChem ID number: 62329046), 7-Propoxy-2,3-dihydro-lH-cyclopenta[b]quinolin- 9-amine (PubChem ID number: 62329207), 2-Methyl-6-propoxyquinolin-4-amine (PubChem ID number: 62329208), 6-Propoxy-2-(trifluoromethyl)quinolin-4-amine (PubChem ID number: 62329381), 3-Ethyl-2-methyl-6-propoxyquinolin-4-amine (PubChem ID number: 62329382), 2-Tert-butyl-6-propoxyquinolin-4-amine (PubChem ID number: 62329541), 2- Ethyl-6-propoxyquinolin-4-amine (PubChem ID number: 62329542), 2-Propan-2-yl-6- propoxyquinolin-4-amine (PubChem ID number: 62329543), 6-Methoxy-8-methyl-2- phenylquinolin-4-amine (PubChem ID number: 62871016), 2-Ethyl-6-methoxy-8- methylquinolin-4-amine (PubChem ID number: 62871377), 6-Methoxy-8-methyl-2-propan- 2-ylquinolin-4-amine (PubChem ID number: 62871378), 7-Methoxy-5-methyl-l, 2,3,4- tetrahydroacridin-9-amine (PubChem ID number: 62871549), 2-(Difluoromethyl)-6-propan- 2-yloxyquinolin-4-amine (PubChem ID number: 62891250), 2-(Difluoromethyl)-6-(2,2,2- trifluoroethoxy)quinolin-4-amine (PubChem ID number: 62891583), 2-(Difluoromethyl)-6- phenoxyquinolin-4-amine (PubChem ID number: 62891595), 2-(Difluoromethyl)-6-ethoxy- N-methylquinolin-4-amine (PubChem ID number: 62892447), 2-(Difluoromethyl)-6- methoxyquinolin-4-amine (PubChem ID number: 62892985), 2-(Difluoromethyl)-6- propoxyquinolin-4-amine (PubChem ID number: 62892986), 2-Methyl-3-propan-2-yl-6- (2,2,2-trifluoroethoxy)quinolin-4-amine (PubChem ID number: 62913284), 2-Methyl-3- propan-2-yl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 62913849), 6- Methoxy-2-methyl-3-propan-2-ylquinolin-4-amine (PubChem ID number: 62914400), 4-(3- Methylquinolin-2-yl)oxyaniline (PubChem ID number: 63228898), 2-Methyl-4-(3- methylquinolin-2-yl)oxyaniline (PubChem ID number: 63228980), 2-Propan-2-yloxy- 7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-l 1-amine (PubChem ID number: 63351282), 2-Ethoxy-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-l 1-amine (PubChem ID number: 63351447), 2-Cyclopropyl-6-phenoxyquinolin-4-amine (PubChem ID number: 63357662), 2- Cyclopropyl-6-propoxyquinolin-4-amine (PubChem ID number: 63357754), 2-Cyclopropyl- N-methyl-6-propoxyquinolin-4-amine (PubChem ID number: 63357795), 2-Cyclopropyl-6- (2,2,2-trifluoroethoxy)quinolin-4-amine (PubChem ID number: 63357829), 2-Cyclopropyl-6- ethoxyquinolin-4-amine (PubChem ID number: 63357967), 2-Cyclopropyl-6- methoxyquinolin-4-amine (PubChem ID number: 63357972), 2-Cyclopropyl-6-ethoxy-N- methylquinolin-4-amine (PubChem ID number: 63358007), 2-Cyclopropyl-6-propan-2- yloxyquinolin-4-amine (PubChem ID number: 63358331), N,2-Dimethyl-6- phenylmethoxyquinolin-4-amine (PubChem ID number: 63479130), N,2-Dimethyl-6- phenoxyquinolin-4-amine (PubChem ID number: 63479304), N-Ethyl-2-methyl-6- phenoxyquinolin-4-amine (PubChem ID number: 63479305), 2-Ethyl-N-methyl-6- phenoxyquinolin-4-amine (PubChem ID number: 63479306), N-Ethyl-6-methoxy-2- phenylquinolin-4-amine (PubChem ID number: 63479475), N-Methyl-2-propyl-6-(2,2,2- trifluoroethoxy)quinolin-4-amine (PubChem ID number: 63479860), 6-Ethoxy-N-methyl-2- phenylquinolin-4-amine (PubChem ID number: 63479867), N,2,3-Trimethyl-6- phenoxyquinolin-4-amine (PubChem ID number: 63479963), 2,3-Dimethyl-6-(4- methylphenoxy)quinolin-4-amine (PubChem ID number: 63479975), N,2-Dimethyl-6-(4- methylphenoxy)quinolin-4-amine (PubChem ID number: 63479976), 6-Ethoxy-3-ethyl-2- methyl-N-propylquinolin-4-amine (PubChem ID number: 63480039), 6-Ethoxy-N-ethyl-2- propylquinolin-4-amine (PubChem ID number: 63480040), 2-Ethyl-6-(4- methylphenoxy)quinolin-4-amine (PubChem ID number: 63480112), 6-Ethoxy-N,2- dipropylquinolin-4-amine (PubChem ID number: 63480205), 2-Tert-butyl-6-ethoxy-N- methylquinolin-4-amine (PubChem ID number: 63480206), 2-Tert-butyl-6-ethoxy-N- ethylquinolin-4-amine (PubChem ID number: 63480207), 2-Tert-butyl-6-ethoxy-N- propylquinolin-4-amine (PubChem ID number: 63480375), 6-Ethoxy-2-ethyl-N- propylquinolin-4-amine (PubChem ID number: 63480376), 6-Ethoxy-2-propan-2-yl-N- propylquinolin-4-amine (PubChem ID number: 63480542), 7-Ethoxy-N-ethyl-l, 2,3,4- tetrahydroacridin-9-amine (PubChem ID number: 63480543), 7-Ethoxy-N-propyl-l, 2,3,4- tetrahydroacridin-9-amine (PubChem ID number: 63480544), 6-Ethoxy-2,3-dimethyl-N- propylquinolin-4-amine (PubChem ID number: 63480714), 6-Ethoxy-N,2-dimethyl-3- propan-2-ylquinolin-4-amine (PubChem ID number: 63480715), 6-Ethoxy-N-ethyl-2-methyl-

3-propan-2-ylquinolin-4-amine (PubChem ID number: 63480716), N-Ethyl-6-propan-2- yloxy-2-propylquinolin-4-amine (PubChem ID number: 63480813), 6-Propan-2-yloxy-N,2- dipropylquinolin-4-amine (PubChem ID number: 63480814), 2-Tert-butyl-N-methyl-6- propan-2-yloxyquinolin-4-amine (PubChem ID number: 63480815), N-Methyl-7-propan-2- yloxy-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 63480816), N-Ethyl-7- propan-2-yloxy-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 63480817), N- Ethyl-2,3-dimethyl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 63480818), 2- Phenyl-8-propoxyquinolin-4-amine (PubChem ID number: 63480885), 6-Ethoxy-2-methyl-3- propan-2-yl-N-propylquinolin-4-amine (PubChem ID number: 63480888), 2-Ethoxy-N- methyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-l 1-amine (PubChem ID number: 63480890), 2-Methyl-6-propan-2-yloxy-N-propylquinolin-4-amine (PubChem ID number: 63480964), 3-Ethyl-N,2-dimethyl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 63480966), N,2-Diethyl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 63480968), 2-Ethyl-6-propan-2-yloxy-N-propylquinolin-4-amine (PubChem ID number: 63480969), 2,3-Dimethyl-6-propan-2-yloxy-N-propylquinolin-4-amine (PubChem ID number: 63480970), 2-Ethoxy-N-ethyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-l 1- amine (PubChem ID number: 63481055), N,3-Diethyl-2-methyl-6-propan-2-yloxyquinolin-

4-amine (PubChem ID number: 63481117), 3-Ethyl-2-methyl-6-propan-2-yloxy-N- propylquinolin-4-amine (PubChem ID number: 63481118), N-Methyl-6-propan-2-yloxy-2- propylquinolin-4-amine (PubChem ID number: 63481119), N-Ethyl-2-propan-2-yl-6-propan- 2-yloxyquinolin-4-amine (PubChem ID number: 63481120), 2-Propan-2-yl-6-propan-2- yloxy-N-propylquinolin-4-amine (PubChem ID number: 63481121), 3-Ethyl-2-methyl-6- phenoxyquinolin-4-amine (PubChem ID number: 63481289), 6-Phenoxy-2-propylquinolin-4- amine (PubChem ID number: 63481290), 6-Phenoxy-2-propan-2-ylquinolin-4-amine (PubChem ID number: 63481291), (2-Ethyl-6-phenoxyquinolin-4-yl)hydrazine (PubChem ID number: 63482073), 2-Phenyl-6-propoxyquinolin-4-amine (PubChem ID number: 63482214), (2,3-Dimethyl-6-phenoxyquinolin-4-yl)hydrazine (PubChem ID number: 63482258), 2-Methyl-6-propoxy-N-propylquinolin-4-amine (PubChem ID number: 63482399), 3-Ethyl-N,2-dimethyl-6-propoxyquinolin-4-amine (PubChem ID number: 63482401), (6-Ethoxy-2-phenylquinolin-4-yl)hydrazine (PubChem ID number: 63482430), N,3-Diethyl-2-methyl-6-propoxyquinolin-4-amine (PubChem ID number: 63482581), 3- Ethyl-2-methyl-6-propoxy-N-propylquinolin-4-amine (PubChem ID number: 63482582), N- Methyl-6-propoxy-2-propylquinolin-4-amine (PubChem ID number: 63482583), N-Ethyl-6- propoxy-2-propylquinolin-4-amine (PubChem ID number: 63482762), 6-Propoxy-N,2- dipropylquinolin-4-amine (PubChem ID number: 63482763), 2-Tert-butyl-N-methyl-6- propoxyquinolin-4-amine (PubChem ID number: 63482764), 2-Tert-butyl-N-ethyl-6- propoxyquinolin-4-amine (PubChem ID number: 63482940), N,2-Diethyl-6- propoxyquinolin-4-amine (PubChem ID number: 63482941), 2-Ethyl-6-propoxy-N- propylquinolin-4-amine (PubChem ID number: 63482942), N-Methyl-2-propan-2-yl-6- propoxyquinolin-4-amine (PubChem ID number: 63483123), N-Ethyl-2-propan-2-yl-6- propoxyquinolin-4-amine (PubChem ID number: 63483124), 2-Propan-2-yl-6-propoxy-N- propylquinolin-4-amine (PubChem ID number: 63483125), N-Methyl-7-propoxy-l, 2,3,4- tetrahydroacridin-9-amine (PubChem ID number: 63483302), N-Ethyl-7-propoxy-l, 2,3,4- tetrahydroacridin-9-amine (PubChem ID number: 63483303), N-Ethyl-2,3-dimethyl-6- propoxyquinolin-4-amine (PubChem ID number: 63483304), 2,3-Dimethyl-6-propoxy-N- propylquinolin-4-amine (PubChem ID number: 63483488), N,2-Dimethyl-3-propan-2-yl-6- propoxyquinolin-4-amine (PubChem ID number: 63483490), (7-Propoxy-l,2,3,4- tetrahydroacridin-9-yl)hydrazine (PubChem ID number: 63483534), N-Ethyl-2-methyl-3- propan-2-yl-6-propoxyquinolin-4-amine (PubChem ID number: 63483667), 2-Propoxy- 7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-l 1-amine (PubChem ID number: 63483849), N-Methyl-2-propoxy-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-l 1-amine (PubChem ID number: 63483850), 6-Methoxy-N,8-dimethyl-2-phenylquinolin-4-amine (PubChem ID number: 63484391), 2-Ethyl-N,3-dimethyl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 63553538), N,2-Diethyl-3-methyl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 63553712), 2-Ethyl-3-methyl-6-propan-2-yloxy-N-propylquinolin-4-amine

(PubChem ID number: 63553713), 2-Ethyl-3-methyl-6-phenoxyquinolin-4-amine (PubChem ID number: 63554081), (2-Ethyl-3-methyl-6-propoxyquinolin-4-yl)hydrazine (PubChem ID number: 63554630), 6-(Difluoromethoxy)-2-ethyl-3-methylquinolin-4-amine (PubChem ID number: 63555157), 2-Ethyl-6-methoxy-3-methylquinolin-4-amine (PubChem ID number: 63555514), 2-Ethyl-3-methyl-6-propoxyquinolin-4-amine (PubChem ID number: 63555858), 2-Ethyl-N,3-dimethyl-6-propoxyquinolin-4-amine (PubChem ID number: 63555859), N,2- Diethyl-3-methyl-6-propoxyquinolin-4-amine (PubChem ID number: 63556037), 2-Ethyl-3- methyl-6-propoxy-N-propylquinolin-4-amine (PubChem ID number: 63556038), (6-Ethoxy-

2-ethyl-3-methylquinolin-4-yl)hydrazine (PubChem ID number: 63556041), 2-Ethyl-3- methyl-6-(2,2,2-trifluoroethoxy)quinolin-4-amine (PubChem ID number: 63561884), 6- Ethoxy-2-ethyl-N,3-dimethylquinolin-4-amine (PubChem ID number: 63562059), 6-Ethoxy- N,2-diethyl-3-methylquinolin-4-amine (PubChem ID number: 63562060), 6-Ethoxy-2-ethyl-

3-methyl-N-propylquinolin-4-amine (PubChem ID number: 63562229), 6-Methoxy-3- methyl-2-(trifluoromethyl)quinolin-4-amine (PubChem ID number: 63743401), 3-Methyl-6- propoxy-2-(trifluoromethyl)quinolin-4-amine (PubChem ID number: 63743402), 6-Ethoxy- 3-methyl-2-(trifluoromethyl)quinolin-4-amine (PubChem ID number: 63743905), 6-Ethoxy- N,3-dimethyl-2-(trifluoromethyl)quinolin-4-amine (PubChem ID number: 63744070), 3- Methyl-6-propan-2-yloxy-2-(trifluoromethyl)quinolin-4-amine (PubChem ID number: 63744926), 3-N-(6-Ethoxyquinolin-4-yl)benzene-l,3-diamine (PubChem ID number: 66487393), 2-Methyl-N-(4-phenoxyphenyl)quinolin-4-amine (PubChem ID number: 67730254), 2-(3-Methoxyphenyl)-6-methylquinolin-4-amine (PubChem ID number: 69205302), 9-Methyl-2-phenylmethoxyacridine (PubChem ID number: 71512148), 2- Methoxy-N-methyl-6-tributylstannylacridin-9-amine (PubChem ID number: 71575093), 2- Methoxy-6-tributylstannylacridin-9-amine (PubChem ID number: 71575183), N-[4-[2- (Dimethylamino)ethoxy]phenyl]-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 72199262), N9-(2,2-Dimethoxyethyl)-7-ethoxyacridine-3,9-diamine (PubChem ID number: 72942188), 4-[6-[2-(2-(18F)Fluoranylethoxy)ethoxy]quinolin-2-yl]aniline (PubChem ID number: 73442979), 4-[6-[2-[2-(2- (18F)Fluoranylethoxy)ethoxy]ethoxy]quinolin-2-yl]aniline (PubChem ID number: 73442980), 4-[6-[2-[2-[2-(2-(18F)Fluoranylethoxy)ethoxy]ethoxy]ethoxy]quinolin-2- yl]aniline (PubChem ID number: 73442981), 4-[6-[2-[2-[2-[2-(2- (18F)Fluoranylethoxy)ethoxy]ethoxy]ethoxy]ethoxy]quinolin-2-yl]aniline (PubChem ID number: 73442982), 4-[6-[2-[2-[2-[2-[2-(2- (18F)Fluoranylethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]quinolin-2-yl]aniline (PubChem ID number: 73442994), 4-[(E)-2-(6-Ethoxy-4-methylquinolin-2-yl)ethenyl]-N,N- dimethylaniline (PubChem ID number: 73891479), 4-[(E)-2-(6-Ethoxy-4-methylquinolin-2- yl)ethenyl]-N,N-diethylaniline (PubChem ID number: 73891480), 2-Methyl-4-[(3- methylphenoxy)methyl]quinoline (PubChem ID number: 78994037), 4-[(3- Ethylphenoxy)methyl]-2-methylquinoline (PubChem ID number: 79232551), [3-[(2- Methylquinolin-4-yl)methoxy]phenyl]methanamine (PubChem ID number: 79234340), 2- Methyl-4-[(2-methylquinolin-4-yl)methoxy]aniline (PubChem ID number: 79234352), 4- Methyl-2-[(2-methylquinolin-4-yl)methoxy]aniline (PubChem ID number: 79234355), 3- Fluoro-4-[(2-methylquinolin-4-yl)methoxy]aniline (PubChem ID number: 79234361), 2- Fluoro-4-[(2-methylquinolin-4-yl)methoxy]aniline (PubChem ID number: 79234370), 2-(2- Methylpropyl)-6-(2,2,2-trifluoroethoxy)quinolin-4-amine (PubChem ID number: 80434060), N-Ethyl-2-(2-methylpropyl)-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 80434096), N-Ethyl-2-(2-methylpropyl)-6-propoxyquinolin-4-amine (PubChem ID number: 80434122), 2-(2-Methylpropyl)-6-propoxyquinolin-4-amine (PubChem ID number: 80439899), N-Methyl-2-(2-methylpropyl)-6-propoxyquinolin-4-amine (PubChem ID number: 80439918), 6-Ethoxy-2-(2-methylpropyl)quinolin-4-amine (PubChem ID number: 80439944), 6-Ethoxy-N-ethyl-2-(2-methylpropyl)quinolin-4-amine (PubChem ID number: 80439963), 6-Ethoxy-N-methyl-2-(2-methylpropyl)quinolin-4-amine (PubChem ID number: 80439981), 2-(2-Methylpropyl)-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 80440085), N-Methyl-2-(2-methylpropyl)-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 80440102), 6-Methoxy-8-methyl-2-(2-methylpropyl)quinolin-4-amine (PubChem ID number: 80440106), 6-Methoxy-2-(2-methylpropyl)quinolin-4-amine (PubChem ID number: 80440140), [6-Ethoxy-2-(2-methylpropyl)quinolin-4-yl]hydrazine (PubChem ID number: 80441132), 2-(3-Methoxyphenyl)quinolin-4-amine (PubChem ID number: 82087395), (2-Methyl-6-propan-2-yloxyquinolin-3-yl)methanamine (PubChem ID number: 82242800), 2-(6-Propan-2-yloxyquinolin-2-yl)ethanamine (PubChem ID number: 82242813), (6-Butoxy-2-methylquinolin-3-yl)methanamine (PubChem ID number: 82244071), [2-Methyl-6-(2-methylpropoxy)quinolin-3-yl]methanamine (PubChem ID number: 82244072), 2-(2-Methyl-6-propan-2-yloxyquinolin-3-yl)ethanamine (PubChem ID number: 82244074), 2-(3-Methyl-6-propan-2-yloxyquinolin-2-yl)ethanamine (PubChem ID number: 82244084), 2-(6-Butoxyquinolin-2-yl)ethanamine (PubChem ID number: 82244088), 2-[6-(2-Methylpropoxy)quinolin-2-yl]ethanamine (PubChem ID number: 82244089), N-Methyl-2-(6-propan-2-yloxyquinolin-2-yl)ethanamine (PubChem ID number: 82244091), 3-(6-Propan-2-yloxyquinolin-2-yl)propan-l-amine (PubChem ID number: 82244093), l-(6-Propan-2-yloxyquinolin-2-yl)propan-2-amine (PubChem ID number: 82244095), 2-(6-Butoxy-2-methylquinolin-3-yl)ethanamine (PubChem ID number: 82245707), 2-[2-Methyl-6-(2-methylpropoxy)quinolin-3-yl]ethanamine (PubChem ID number: 82245708), 3-(2-Methyl-6-propan-2-yloxyquinolin-3-yl)propan-l-amine (PubChem ID number: 82245715), 2-(6-Butoxy-3-methylquinolin-2-yl)ethanamine (PubChem ID number: 82245717), 2-[3-Methyl-6-(2-methylpropoxy)quinolin-2-yl]ethanamine (PubChem ID number: 82245718), 2-(6-Butoxyquinolin-2-yl)-N-methylethanamine (PubChem ID number: 82245725), (2-Methyl-6-phenoxyquinolin-3-yl)methanamine (PubChem ID number: 82246665), 2-(6-Phenoxyquinolin-2-yl)ethanamine (PubChem ID number: 82246669), 3-(6- Butoxy-2-methylquinolin-3-yl)propan-l -amine (PubChem ID number: 82247732), 3-[2- Methyl-6-(2-methylpropoxy)quinolin-3-yl]propan-l -amine (PubChem ID number: 82247733), 2-(6-Butoxy-3-methylquinolin-2-yl)-N-methylethanamine (PubChem ID number: 82247735), 2-(2-Aminoethyl)-N,N-dimethyl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 82247856), 3-(Aminomethyl)-N,N,2-trimethyl-6-propan-2-yloxyquinolin-4- amine (PubChem ID number: 82247860), (2-Methyl-6-phenylmethoxyquinolin-3- yl)methanamine (PubChem ID number: 82248764), 2-(2-Methyl-6-phenoxyquinolin-3- yl)ethanamine (PubChem ID number: 82248765), N-Methyl-l-(2-methyl-6-phenoxyquinolin- 3-yl)methanamine (PubChem ID number: 82248767), (3-Methyl-6-phenylmethoxyquinolin-

2-yl)methanamine (PubChem ID number: 82248769), 2-(3-Methyl-6-phenoxyquinolin-2- yl)ethanamine (PubChem ID number: 82248770), 2-(6-Phenylmethoxyquinolin-2- yl)ethanamine (PubChem ID number: 82248774), N-Methyl-2-(6-phenoxyquinolin-2- yl)ethanamine (PubChem ID number: 82248775), 3-(6-Phenoxyquinolin-2-yl)propan-l- amine (PubChem ID number: 82248777), l-(6-Phenoxyquinolin-2-yl)propan-2-amine (PubChem ID number: 82248779), 2-(2-Aminoethyl)-6-butoxy-N,N-dimethylquinolin-4- amine (PubChem ID number: 82250140), 2-(2-Aminoethyl)-N,N-dimethyl-6-(2- methylpropoxy)quinolin-4-amine (PubChem ID number: 82250141), N,N-Dimethyl-2-[2- (methylamino)ethyl]-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 82250146),

3-(Aminomethyl)-6-butoxy-N,N,2-trimethylquinolin-4-amine (PubChem ID number: 82250148), 3-(Aminomethyl)-N,N,2-trimethyl-6-(2-methylpropoxy)quinolin-4-amine (PubChem ID number: 82250149), 3-(2-Aminoethyl)-N,N,2-trimethyl-6-propan-2- yloxyquinolin-4-amine (PubChem ID number: 82250151), 2-(2-Methyl-6- phenylmethoxyquinolin-3-yl)ethanamine (PubChem ID number: 82251044), N-Methyl-l-(2- methyl-6-phenylmethoxyquinolin-3-yl)methanamine (PubChem ID number: 82251045), N- Methyl-2-(2-methyl-6-phenoxyquinolin-3-yl)ethanamine (PubChem ID number: 82251046), 3-(2-Methyl-6-phenoxyquinolin-3-yl)propan-l-amine (PubChem ID number: 82251048), 2- (3-Methyl-6-phenylmethoxyquinolin-2-yl)ethanamine (PubChem ID number: 82251050), N- Methyl-2-(3-methyl-6-phenoxyquinolin-2-yl)ethanamine (PubChem ID number: 82251052), N-Methyl-2-(6-phenylmethoxyquinolin-2-yl)ethanamine (PubChem ID number: 82251054), 2-Methyl-3-(6-phenoxyquinolin-2-yl)propan-l -amine (PubChem ID number: 82251055), 2- Methyl-6-phenylmethoxyquinoline-4-carboximidamide (PubChem ID number: 82573520), (4-Methyl-6-phenylmethoxyquinolin-2-yl)methanamine (PubChem ID number: 82573663), (2-Methyl-6-phenylmethoxyquinolin-4-yl)methanamine (PubChem ID number: 82573691), 2-(6-Ethoxy-4-methylquinolin-2-yl)ethanamine (PubChem ID number: 82575555), 2-(6- Butoxy-4-methylquinolin-2-yl)ethanamine (PubChem ID number: 82575577), 2-[4-Methyl- 6-(2-methylpropoxy)quinolin-2-yl]ethanamine (PubChem ID number: 82575578), 2-(4- Methyl-6-phenylmethoxyquinolin-2-yl)ethanamine (PubChem ID number: 82575582), 2-(6- Ethoxy-2-methylquinolin-4-yl)ethanamine (PubChem ID number: 82575607), 2-(6-Butoxy- 2-methylquinolin-4-yl)ethanamine (PubChem ID number: 82575629), 2-(2-Methyl-6- phenylmethoxyquinolin-4-yl)ethanamine (PubChem ID number: 82575634), l-(4-Methyl-6- phenylmethoxyquinolin-2-yl)ethanamine (PubChem ID number: 82575808), l-(2-Methyl-6- phenylmethoxyquinolin-4-yl)ethanamine (PubChem ID number: 82575840), 3-(6-Ethoxy-4- methylquinolin-2-yl)propan-l -amine (PubChem ID number: 82576604), 3-(6-Butoxy-4- methylquinolin-2-yl)propan-l -amine (PubChem ID number: 82576626), 3-(4-Methyl-6- phenylmethoxyquinolin-2-yl)propan-l -amine (PubChem ID number: 82576631), 3-(6- Ethoxy-2-methylquinolin-4-yl)propan-l -amine (PubChem ID number: 82576655), 3-(6- Butoxy-2-methylquinolin-4-yl)propan-l -amine (PubChem ID number: 82576677), 3-(2- Methyl-6-phenylmethoxyquinolin-4-yl)propan-l -amine (PubChem ID number: 82576682), 2-Methyl-3-(4-methyl-6-phenylmethoxyquinolin-2-yl)propan-l -amine (PubChem ID number: 82576857), 2-Methyl-3-(2-methyl-6-phenylmethoxyquinolin-4-yl)propan-l -amine (PubChem ID number: 82576910), 2,2-Dimethyl-3-(4-methyl-6-phenylmethoxyquinolin-2- yl)propan-l -amine (PubChem ID number: 82577077), 2,2-Dimethyl-3-(2-methyl-6- phenylmethoxyquinolin-4-yl)propan-l -amine (PubChem ID number: 82577130), l-(6- Methoxy-4-methylquinolin-2-yl)-2-methylpropan-2-amine (PubChem ID number: 82577276), l-(6-Ethoxy-4-methylquinolin-2-yl)-2-methylpropan-2-amine (PubChem ID number: 82577285), l-(6-Butoxy-4-methylquinolin-2-yl)-2-methylpropan-2-amine (PubChem ID number: 82577307), 2-Methyl-l-[4-methyl-6-(2-methylpropoxy)quinolin-2- yl]propan-2-amine (PubChem ID number: 82577308), 2-Methyl-l-[4-methyl-6-[(2- methylpropan-2-yl)oxy]quinolin-2-yl]propan-2-amine (PubChem ID number: 82577309), 2- Methyl-l-(4-methyl-6-phenylmethoxyquinolin-2-yl)propan-2-amine (PubChem ID number: 82577312), l-(6-Ethoxy-2-methylquinolin-4-yl)-2-methylpropan-2-amine (PubChem ID number: 82577338), l-(6-Butoxy-2-methylquinolin-4-yl)-2-methylpropan-2-amine (PubChem ID number: 82577360), 2-Methyl-l-[2-methyl-6-(2-methylpropoxy)quinolin-4- yl]propan-2-amine (PubChem ID number: 82577361), 2-Methyl-l-(2-methyl-6- phenylmethoxyquinolin-4-yl)propan-2-amine (PubChem ID number: 82577365), l-(6- Ethoxy-4-methylquinolin-2-yl)propan-2-amine (PubChem ID number: 82577517), l-(6- Butoxy-4-methylquinolin-2-yl)propan-2-amine (PubChem ID number: 82577539), l-(4- Methyl-6-phenylmethoxyquinolin-2-yl)propan-2-amine (PubChem ID number: 82577544), l-(6-Ethoxy-2-methylquinolin-4-yl)propan-2-amine (PubChem ID number: 82577569), l-(2- Methyl-6-phenylmethoxyquinolin-4-yl)propan-2-amine (PubChem ID number: 82577596), 4-(6-Ethoxy-4-methylquinolin-2-yl)butan-l -amine (PubChem ID number: 82577746), 4-(6- Butoxy-4-methylquinolin-2-yl)butan-l -amine (PubChem ID number: 82577768), 4-(4- Methyl-6-phenylmethoxyquinolin-2-yl)butan-l -amine (PubChem ID number: 82577773), 4- (6-Ethoxy-2-methylquinolin-4-yl)butan-l -amine (PubChem ID number: 82577798), 4-(6- Butoxy-2-methylquinolin-4-yl)butan-l -amine (PubChem ID number: 82577820), 4-(2- Methyl-6-phenylmethoxyquinolin-4-yl)butan-l -amine (PubChem ID number: 82577825), 2- (2 -Methylquinolin-6-yl)oxy ethanamine (PubChem ID number: 82580525), 3-(2- Methylquinolin-6-yl)oxypropan-l -amine (PubChem ID number: 82580728), 3 -(2,4- Dimethylquinolin-6-yl)oxypropan-l -amine (PubChem ID number: 82580734), 4-(2- Methylquinolin-6-yl)oxybutan-l -amine (PubChem ID number: 82580752), 4-(2,4- Dimethylquinolin-6-yl)oxybutan-l -amine (PubChem ID number: 82580758), 2-Methyl-6- phenylmethoxyquinoline (PubChem ID number: 82580854), 6-Butoxy-N,N,2- trimethylquinolin-4-amine (PubChem ID number: 82581246), 4-Ethoxy-2-methylquinolin-7- amine (PubChem ID number: 84222112), 4-Amino-6-propan-2-yloxyquinoline-2-carbonitrile (PubChem ID number: 84625282), 2-(6-Propan-2-yloxyquinolin-2-yl)propan-l -amine (PubChem ID number: 84631354), 2-(4-Methyl-6-propan-2-yloxyquinolin-2-yl)ethanamine (PubChem ID number: 84631355), 2-(3-Methyl-6-propan-2-yloxyquinolin-2-yl)propan-l- amine (PubChem ID number: 84637220), N-Benzyl-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 85520221), 6-Ethoxy-2-(4-ethylphenyl)quinoline (PubChem ID number: 85539040), 6-Butoxy-2-(4-ethylphenyl)quinoline (PubChem ID number: 85539041), 6-Butoxy-2-(4-butylphenyl)quinoline (PubChem ID number: 85539043), 6- Butoxy-2-(4-pentylphenyl)quinoline (PubChem ID number: 85539044), 2-Phenyl-3-hexyl-6- ethoxyquinoline (PubChem ID number: 86241105), 13-Oxa-2- azatetracyclo[8.5.0.03,8.012,14]pentadeca-l(15),2,4,6,8,10,12(14)-heptaene-5,9-diamine (PubChem ID number: 88673642), 6-Ethoxy-2-[(Z)-2-phenylethenyl]quinoline (PubChem ID number: 92236678), N'-(6-Ethoxy-2-methylquinolin-4-yl)ethane-l,2-diamine (PubChem ID number: 100129617), N'-(6-Ethoxy-2-methylquinolin-4-yl)propane-l,3-diamine (PubChem ID number: 100129630), N'-(6-Ethoxy-2-methylquinolin-4-yl)-N-methylpropane-l,3- diamine (PubChem ID number: 100129642), N'-(2-Methyl-6-phenoxyquinolin-4-yl)ethane- 1,2-diamine (PubChem ID number: 100129656), N'-(2-Methyl-6-phenoxyquinolin-4- yl)propane- 1,3 -diamine (PubChem ID number: 100129671), N-Methyl-N'-(2-methyl-6- phenoxyquinolin-4-yl)propane- 1,3 -diamine (PubChem ID number: 100129685), 2-Ethoxy-5- iodo-6-amino-9-chloroacridine (PubChem ID number: 101025374), 2-Phenyl-4-methyl-6- ethoxyquinoline (PubChem ID number: 101854034), 2-Phenyl-3-pentyl-6-ethoxyquinoline (PubChem ID number: 102178278), 2-Ethyl-7-fluoro-6-methoxyquinolin-4-amine (PubChem ID number: 103996734), 7-Fluoro-6-methoxy-2-propylquinolin-4-amine (PubChem ID number: 103996735), 6-Fluoro-7-methoxy-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 103996747), 7-Fluoro-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 103996754), 7-Fluoro-6-methoxy-N-methyl-2-phenylquinolin-4-amine (PubChem ID number: 103996768), 7-Fluoro-6-methoxy-2-propan-2-ylquinolin-4-amine (PubChem ID number: 103996775), 7-Fluoro-6-methoxy-2-phenylquinolin-4-amine (PubChem ID number: 103996782), 2-Cyclopentyl-6-ethoxy-N-methylquinolin-4-amine (PubChem ID number: 104244338), 2-Cyclopentyl-6-ethoxyquinolin-4-amine (PubChem ID number: 104244340), 2-Cyclopentyl-6-propan-2-yloxyquinolin-4-amine (PubChem ID number: 104244485), 2- Cyclopentyl-6-methoxyquinolin-4-amine (PubChem ID number: 104244506), 2-Cyclopentyl- N-methyl-6-propoxyquinolin-4-amine (PubChem ID number: 104244547), 2-Cyclopentyl-6- propoxyquinolin-4-amine (PubChem ID number: 104244548), 6-Ethoxy-7-fluoro-N,2- dimethylquinolin-4-amine (PubChem ID number: 104326735), 7-Ethoxy-6-fluoro-l, 2,3,4- tetrahydroacridin-9-amine (PubChem ID number: 104326736), 6-Ethoxy-7-fluoro-2- methylquinolin-4-amine (PubChem ID number: 104326740), 6-Ethoxy-2-ethyl-7-fluoro-N- methylquinolin-4-amine (PubChem ID number: 104326741), 6-Ethoxy-7-fluoro-2-propan-2- ylquinolin-4-amine (PubChem ID number: 104326743), 6-Ethoxy-7-fluoro-N-methyl-2- propylquinolin-4-amine (PubChem ID number: 104326754), 6-Ethoxy-7-fluoro-2- propylquinolin-4-amine (PubChem ID number: 104326755), 6-Ethoxy-7-fluoro-2-methyl-3- propan-2-ylquinolin-4-amine (PubChem ID number: 104326756), 2-(Difluoromethyl)-6- ethoxy-7-fluoroquinolin-4-amine (PubChem ID number: 104326761), 6-Ethoxy-7-fluoro-2- phenylquinolin-4-amine (PubChem ID number: 104326767), 6-Ethoxy-7-fluoro-2,3- dimethylquinolin-4-amine (PubChem ID number: 104326771), 6-Ethoxy-7-fluoro-2-(2- methylpropyl)quinolin-4-amine (PubChem ID number: 104326775), 2-Cyclopentyl-6- ethoxy-7-fluoroquinolin-4-amine (PubChem ID number: 104326776), 6-Ethoxy-7-fluoro-2- (trifluoromethyl)quinolin-4-amine (PubChem ID number: 104326778), 2-Tert-butyl-6- ethoxy-7-fluoroquinolin-4-amine (PubChem ID number: 104326786), 6-Ethoxy-2-ethyl-7- fluoroquinolin-4-amine (PubChem ID number: 104326790), 6-Ethoxy-7-fluoro-3-methyl-2- (trifluoromethyl)quinolin-4-amine (PubChem ID number: 104326796), 2-Cyclopropyl-6- ethoxy-7-fluoroquinolin-4-amine (PubChem ID number: 104326798), 6-Ethoxy-3-methyl-2- phenylquinolin-4-amine (PubChem ID number: 104846959), 6-Methoxy-3-methyl-2- phenylquinolin-4-amine (PubChem ID number: 104847039), 6-Methoxy-N,3-dimethyl-2- phenylquinolin-4-amine (PubChem ID number: 104847040), 6-Methoxy-3,8-dimethyl-2- phenylquinolin-4-amine (PubChem ID number: 104847065), 7-Fluoro-6-methoxy-3-methyl- 2-phenylquinolin-4-amine (PubChem ID number: 104847088), 8-Ethoxy-3,4-dihydro-lH- pyrano[4,3-b]quinolin-10-amine (PubChem ID number: 106472983), 8-Propan-2-yloxy-3,4- dihydro-lH-pyrano[4,3-b]quinolin-10-amine (PubChem ID number: 106473175), 8-Propoxy- 3,4-dihydro-lH-pyrano[4,3-b]quinolin-10-amine (PubChem ID number: 106473261), N- Tert-butyl-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 110433204), 6- Methoxy-2-methyl-N-(l-phenylcyclopropyl)quinolin-4-amine (PubChem ID number: 110433206), 8-Methoxy-2-methyl-N-(4-propoxyphenyl)quinolin-4-amine (PubChem ID number: 110435581), N-(3,5-Dimethylphenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 110435670), N-(2-Fluorophenyl)-6-methoxy-2-methylquinolin-4- amine (PubChem ID number: 110435671), 6-Methoxy-2-methyl-N-(4-propan-2- yloxyphenyl)quinolin-4-amine (PubChem ID number: 110435675), N-[3-[(6-Methoxy-2- methylquinolin-4-yl)amino]phenyl]acetamide (PubChem ID number: 110435676), N-(3- Fluorophenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 110435680), 6- Methoxy-2-methyl-N-(2-propoxyphenyl)quinolin-4-amine (PubChem ID number: 110435685), 6-Methoxy-2-methyl-N-(4-propoxyphenyl)quinolin-4-amine (PubChem ID number: 110435686), l-N-(6-Methoxy-2-methylquinolin-4-yl)-3-N,3-N-dimethylbenzene- 1,3-diamine (PubChem ID number: 110435694), 6-Methoxy-2-methyl-N-(4-methyl-3- nitrophenyl)quinolin-4-amine (PubChem ID number: 110435695), N-(4-Ethyl-3- nitrophenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 110435696), N- [3-[(6-Methoxy-2-methylquinolin-4-yl)amino]-4-methylphenyl]acetamide (PubChem ID number: 110435697), N-(3,4-Difluorophenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 110435699), 6-Methoxy-2-methyl-N-(2,3,4-trifluorophenyl)quinolin- 4-amine (PubChem ID number: 110435700), N-(2,6-Difluorophenyl)-6-methoxy-2- methylquinolin-4-amine (PubChem ID number: 110435701), N-(2,5-Difluorophenyl)-6- methoxy-2-methylquinolin-4-amine (PubChem ID number: 110435702), N-(2,4- Difluorophenyl)-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 110435703), N-[(3-Ethoxyphenyl)methyl]-2-methylquinolin-4-amine (PubChem ID number: 112838597), 2-Phenyl-6-phenylmethoxyquinolin-4-amine (PubChem ID number: 113232549), N-Ethyl-7- phenylmethoxy-2,3-dihydro-lH-cyclopenta[b]quinolin-9-amine (PubChem ID number: 113232550), N-Ethyl-7-phenylmethoxy-l,2,3,4-tetrahydroacridin-9-amine (PubChem ID number: 113232551), 2,3-Dimethyl-6-phenylmethoxy-N-propylquinolin-4-amine (PubChem ID number: 113232552), 6-Ethoxy-3-ethyl-7-fluoro-2-methylquinolin-4-amine (PubChem ID number: 113399809), 6-Ethoxy-2-ethyl-7-fluoro-3-methylquinolin-4-amine (PubChem ID number: 113399810), 8-Methoxy-3,4-dihydro-lH-pyrano[4,3-b]quinolin-10-amine (PubChem ID number: 113838676), 5-Fluoro-2-methyl-4-(quinolin-2-ylmethoxy)aniline (PubChem ID number: 114415719), 5-Fluoro-2-methyl-4-(2-methylquinolin-4-yl)oxyaniline (PubChem ID number: 114417606), 5-Fluoro-2-methyl-4-(3-methylquinolin-2-yl)oxyaniline (PubChem ID number: 114417691), Quinoline, 2-methyl-6-propoxy- (PubChem ID number: 119093576), 3-Iodo-6-methoxy-2-methylquinolin-4-amine (PubChem ID number: 121236710), 6-Ethoxy-3-iodo-2-methylquinolin-4-amine (PubChem ID number: 121236730), 6-Ethoxy-2-phenyl-4-piperazin-l-ylquinoline (PubChem ID number: 121237042), 4-(6-Ethoxyquinolin-2-yl)-N,N-dimethylaniline (PubChem ID number: 125465220), N-[4-[(2S)-l-Methoxypropan-2-yl]oxyphenyl]-2,6,8-trimethylquinolin-4-amine (PubChem ID number: 125494142), N-[4-[(2R)-l-Methoxypropan-2-yl]oxyphenyl]-2,6,8- trimethylquinolin-4-amine (PubChem ID number: 125494143), 2-Ethoxy-4-methylquinolin- 7-amine (PubChem ID number: 130017004), N-(4-Methoxyphenyl)-2,4- bis(trifluoromethyl)quinolin-7-amine (PubChem ID number: 132507914), N-Ethyl-2- (methoxymethyl)-6-phenylmethoxyquinolin-4-amine (PubChem ID number: 133659010), 2- Prop-2-enoxyquinolin-7-amine (PubChem ID number: 134110893), 2 -Ethoxy-6- [(4- methoxyphenyl)methylideneamino]acridin-10-ium-9-amine (PubChem ID number: 135591706), 2-Methoxy-10-methylacridin-10-ium-3,6-diamine (PubChem ID number: 139844118), l-[2-(4-Aminophenyl)quinolin-6-yl]oxybutan-2-ol (PubChem ID number: 144371573), 2,3-Bis(ethenyl)-N-(4-methoxyphenyl)quinolin-4-amine (PubChem ID number: 144507984), 6-Cyclohexyloxy-2-ethylquinoline (PubChem ID number: 144562485), 2-[2-[2- [2-(4-Aminophenyl)quinolin-6-yl]oxyethoxy]ethoxy]ethoxy thiohypoiodite (PubChem ID number: 146581016), 2-(3-Methoxyphenyl)-4-N-(4-methoxyphenyl)quinoline-4,7-diamine (PubChem ID number: 146625238), 7-N-(4-Methoxyphenyl)-2-(4-methylphenyl)quinoline- 4,7-diamine (PubChem ID number: 146625255), 2-Fluoro-6-methoxyquinolin-4-amine (PubChem ID number: 149732601).

Claims

CLAIMS What is claimed is:

Claim 1. A pharmaceutical composition comprising ethacridine or a derivative thereof, for use in a method of treating a viral infection in a subject.

Claim 2. The pharmaceutical composition of Claim 1, wherein the viral infection is a coronavirus infection.

Claim 3. The pharmaceutical composition of Claim 2, wherein the viral infection is COVID-19.

Claim 4. The pharmaceutical composition of Claim 1, wherein the pharmaceutical composition comprises ethacridine.

Claim 5. The pharmaceutical composition of Claim 1, wherein the pharmaceutical composition comprises a derivative of ethacridine, wherein the derivative of ethacridine comprises

wherein Ri and R2 may be any of: an amine, hydrogen, or a group selected from acylamino, dialkylamino, cycloalkylamino, azacycloalkyl, alkylcycloalkylamino, aroylamino, diarylamino, arylalkylamino, aralkylamino, alkylaralkylamino, arylaralkylamino, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkoxy, perfluoro alkoxy, mercapto, alkylthio, arylthio, aralkylthio, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, hydroxysulfonyl, amidosulfonyl, dialkylamidosulfonyl, arylalkylamidosulfonyl, formyl, acyl, aroyl, alkyl, alkylene, alkenyl, aryl, aralkyl, vinyl, or alkynyl groups; and wherein R3 may be any of: an aryl ethyl ether, hydrogen, or a group selected from acylamino, dialkylamino, cycloalkylamino, azacycloalkyl, alkylcycloalkylamino, aroylamino, diarylamino, arylalkylamino, aralkylamino, alkylaralkylamino, arylaralkylamino, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkoxy, perfluoro alkoxy, mercapto, alkylthio, arylthio, aralkylthio, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, hydroxysulfonyl, amidosulfonyl, dialkylamidosulfonyl, arylalkylamidosulfonyl, formyl, acyl, aroyl, alkyl, alkylene, alkenyl, aryl, aralkyl, vinyl, or alkynyl groups.

Claim 6. A pharmaceutical composition comprising an antiviral agent selected from the group consisting of: artesunate; bexarotene; butoconazole; candesartan; cinacalcet; elvitegravir; nifuroxazide; sertaconazole; sulconazole; verteporfm; and a derivative of the foregoing, for use in a method of inhibiting the activity of a viral protease.

Claim 7. The pharmaceutical composition of Claim 6, wherein the viral protease is the SARS-CoV-2 Main viral protease.

Claim 8. A method of treating a viral infection in a subject in need of treatment therefor, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising ethacridine or a derivative thereof.

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Claim 9. The method of Claim 6, wherein the viral infection is infection by a coronavirus.

Claim 10. The method of Claim 7, wherein the viral infection is COVID-19.

Claim 11. The method of Claim 8, wherein the pharmaceutical agent comprises ethacridine.

Claim 12. The method of Claim 8, wherein the pharmaceutical composition comprises a derivative of ethacridine, wherein the derivative of ethacridine comprises

Claim 13. The method of Claim 8, wherein the treatment is a preventative treatment.

Claim 14. The method of Claim 8, wherein the subject has or is suspected of having the viral infection.

Claim 15. The method of Claim 8, wherein the administration is by injection.

Claim 16. The method of Claim 8, wherein the administration is by aerosol delivery to the airway of the subject.

Claim 17. A method of inhibiting the activity of a viral protease in a subject at risk of or suffering from a viral infection, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an agent selected from the group consisting of artesunate, bexarotene, butoconazole, candesartan, cinacalcet, elvitegravir, nifuroxazide, sertaconazole, sulconazole, verteporfin, and a derivative of the foregoing.

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Claim 18. The method of Claim 17, wherein the viral infection is infection by a coronavirus.

Claim 19. The method of Claim 18, wherein the coronavirus is SARS-CoV-2 and the protease is Mpro.

Claim 20. A drug delivery device, comprising a device loaded with a pharmaceutical composition comprising ethacridine or a derivative thereof, wherein the device is configured to deliver a therapeutically effective amount of the pharmaceutical composition to the subject.

Claim 21. The drug delivery device of Claim 20, wherein the device is configured for aerosol delivery.

Claim 22. The drug delivery device of Claim 21, wherein the device comprises a dry powder inhaler, metered-dose inhaler, nebulizer, mechanical ventilator, or adaptive aerosol device.

Claim 23. A viral protease reporter, comprising a fusion protein comprising the domains of a fluorescent proteins wherein one or more domains of the fluorescent protein is configured in an inactive state and further comprising a viral protease cleavage site, wherein cleavage of the fusion protein by the target protease liberates the one or more domains to assume an active conformation, resulting in a fluorescent signal, wherein the reporter is configured to be activated by cleavage by SARS-CoV-2 Mpro.