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WO2025116843A1 - Substance active ciblant le stade sanguin asexué contre le paludisme - Google Patents

Substance active ciblant le stade sanguin asexué contre le paludisme Download PDF

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Publication number
WO2025116843A1
WO2025116843A1 PCT/TR2024/050124 TR2024050124W WO2025116843A1 WO 2025116843 A1 WO2025116843 A1 WO 2025116843A1 TR 2024050124 W TR2024050124 W TR 2024050124W WO 2025116843 A1 WO2025116843 A1 WO 2025116843A1
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WO
WIPO (PCT)
Prior art keywords
malaria
treatment
compound
targets
inhibition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/TR2024/050124
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English (en)
Inventor
Ahmet Burak DOGANOGLU
Vildan ENISOGLU ATALAY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TC Uskudar Universitesi
Original Assignee
TC Uskudar Universitesi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from TR2023/016027 external-priority patent/TR2023016027A2/tr
Application filed by TC Uskudar Universitesi filed Critical TC Uskudar Universitesi
Publication of WO2025116843A1 publication Critical patent/WO2025116843A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to a compound targeting the asexual blood stage for use in the treatment of malaria. Said compound follows a different pathway than resistance mechanisms and prevents the disease from gaining resistance to this compound.
  • Malaria is a disease caused by 5 different Plasmodium parasites. Said parasite can be transmitted to humans through female mosquitoes. The disease, which can be transmitted from people with malaria to healthy people, is among the top 30 causes of death in the world, especially in developing countries. After the parasites that cause malaria enter the human blood, the parasites quickly settle in the liver cells. During this settlement, after asexual reproduction of all types of Plasmodium parasites, merozoites exit the liver and invade erythrsoids, initiating the symptomatic phase of malaria [1 ]. Malaria disease, which progresses in attacks, begins to show its symptoms approximately 1 -2 weeks after exposure to the parasite. In the majority of these attacks, patients experience tremors, high fever and loss of consciousness.
  • Malaria disease causes liver damage and causes paralysis and death [2]. Microbial tests to detect the presence of Plasmodium parasites in blood samples taken from patients are used to diagnose people with malaria. Treatment of people with these parasites is of great importance in preventing the progression of the disease and saving the lives of patients. In current treatments, appropriate antimalarial methods are determined according to the type of Plasmodium parasite in the patient's blood and the patient's condition.
  • antimalarial drugs containing the active ingredients chloroquine, quinine, doxycycline, atovaquone/proguanil, mefloquine and artemisinin are commonly used in the treatment of malaria.
  • Plasmodium parasites have developed resistance to all of these antimalarial drugs [3], and the gradual increase in this resistance makes malaria a major threat. This causes the treatment to be interrupted and may even lead to treatment failure.
  • patients whose treatment is completed begin to show malaria attacks and other symptoms again within approximately three to four months following the end of treatment, although they continue their lives asymptomatically for a while [4].
  • mentioned antimalarial drugs have become insufficient in the treatment of malaria, and therefore new treatment methods and drugs are needed in the treatment of malaria.
  • the utility model numbered US10183066B2 in the state of the art describes a vaccine used against Plasmodium parasites, especially Plasmodium falciparum, which causes malaria.
  • This vaccine contains recombinant proteins and/or combinations of recombinant fusion proteins against the numerous surface proteins of the Plasmodium falciparum parasite.
  • said vaccine contains antigens from the surface proteins of the pre-erythrocyte, blood and sexual stages of the parasite's life cycle.
  • the vaccine described in this patent does not have therapeutic properties. This vaccine only protects people who have not been exposed to the Plasmodium falciparum parasite and has lower protection against other Plasmodium parasites that cause malaria. Therefore, the vaccine described in said patent document is insufficient to treat people with malaria.
  • the invention discloses an active substance that targets the asexual blood stage for use in the treatment of malaria.
  • Said active substance is 1 ,1 -dioxo-2-(3-propylphenyl)- 4-[[3-[( 1 S)-1 -sulfanylethyl]phenyl]methyl]-1
  • A6,2,4-benzothiadiazin-3-on compound obtained by derivatisation of the structure named MMV008173 and is shown with Formula I.
  • An aim of the invention is to provide effective malaria treatment by following a different pathway from the pathway in which malaria-causing parasites acquire resistance to currently used drugs.
  • a compound that uses pathways to which malaria parasites are not resistant is used to be used in the treatment of malaria.
  • 1 , 1 -dioxo-2-(3-propylphenyl)-4-[[3-[(1 S)-1 - sulfanylethyl]phenyl]methyl]-1A6,2,4-benzothiadiazin-3-on compound performs the treatment by providing competitive inhibition of 4 different merozoite surface proteins, which act on the invasion of erythrocytes by merozoites.
  • the invention aims to increase this inhibition percentage to higher values by derivatising the MMV008173 structure, which inhibits the parasites that cause malaria by binding to their surface proteins. Since the MMV008173 structure has a resistance mechanism, an effective treatment in malaria is aimed by interacting with the merozoite surface proteins of the MMV008173 derivative compound that is the subject of the invention and regulating the feature that causes the MMV008173 molecule to face resistance.
  • Figure 1 The interaction maps of the molecule in the active site of the protein as a result of the docking study of the MSP1 - 1 ,1 -dioxo-2-(3-propylphenyl)-4-[[3-[(1 S)-1 - sulfanylethyl]phenyl]methyl]-1A6,2,4-benzothiadiazin-3-on molecule
  • Figure 2 The interaction maps of the molecule in the active site of the protein as a result of the docking study of the PvDBP- 1 ,1 -dioxo-2-(3-propylphenyl)-4-[[3-[(1 S)-1 - sulfanylethyl]phenyl]methyl]-1A6,2,4-benzothiadiazin-3-on molecule
  • Figure 3 The interaction maps of the molecule in the active site of the protein as a result of the docking study of the RH5-1 - 1 -dioxo-2-(3-propylphenyl)-4-[[3-[(1 S)-1 - sulfanylethyl]phenyl]methyl]-1A6,2,4-benzothiadiazin-3-on molecule
  • Figure 4 The interaction maps of the molecule in the active site of the protein as a result of the docking study of the AMA1 -1 - 1 -dioxo-2-(3-propylphenyl)-4-[[3-[(1 S)-1 - sulfanylethyl]phenyl]methyl]-1A6,2,4-benzothiadiazin-3-on molecule Detailed Description of the Invention
  • the invention relates to an active ingredient to be used in the treatment of malaria by inhibiting multiple proteins.
  • Said active substance represented by formula I is 1 ,1 - dioxo-2-(3-propylphenyl)-4-[[3-[(1 S)-1 -sulfanylethyl]phenyl]methyl]-1A6,2,4- benzothiadiazin-3-on.
  • the compound of the invention targets 4 different merozoite surface proteins named MSP1 , PvDBP, RH5 and AMA1 and provides treatment of the disease by inhibiting these proteins.
  • Said proteins named MSP1 (Merozoite Surface Protein 1 ), PvDBP (Plasmodium vivax Duffy Binding Protein), RH5 (Reticulocyte binding protein Homolog 5) and AMA1 (Apical Membrane Antigen 1 ) are found on the surface of Plasmodium parasites that cause malaria. After malaria enters the human body and proliferates asexually in the liver, merozoites exit the liver and invade erythrocytes.
  • MMV008173 one of the compounds examined in the Malaria Box set, showed 97% inhibition in the 3D7 wild type strain, more than the approximately 70- 80% inhibition expected from an invasion inhibitor, and also showed 76% inhibition with a 21 % decrease in the DD2 resistant strain.
  • the compound MMV008173 shown by Formula II acts inside the cell due to the decrease in inhibition in the DD2 strain, although there is no resistance mechanism.
  • the MMV008173 molecule acts within the cell and attaches to the existing resistance mechanism.
  • the studies in the state of the art [6,7] are examined for comparison, it is shown that the MMV020291 invasion inhibitor has no effect after invasion and does not interfere with resistance mechanisms.
  • MMV008173 ligand binds with MSP1 , DBP, RH5 and AMA1 proteins, showing 76% inhibition (DD2 strain), and then, the inhibited MSP1 protein, which is incorporated into the structure of the food vacuole membrane formed through endocytosis, cannot act within the cell and increases the inhibition rate to 97% (3D7 strain).
  • the compound MMV008173 bound to the MSP1 protein is disconnected and thrown out of the cell, and MSP1 cannot inhibit it.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé qui réalise un traitement par une méthode d'inhibition multiprotéique destiné à être utilisé dans le traitement du paludisme. Ledit composé suit une voie différente de la voie dans laquelle une résistance aux médicaments survient dans le traitement du paludisme et cible des protéines de surface appelées MSP1, PvDBP, RH5 et AMA1. Au moyen de la liaison à ces protéines de surface avec une affinité de -7,60, -8,10, -6,80 et -9,00 (kcal/mol), respectivement, une alternative à la résistance aux médicaments rencontrée dans le traitement du paludisme a été obtenue avec 97 % d'inhibition.
PCT/TR2024/050124 2023-11-29 2024-02-16 Substance active ciblant le stade sanguin asexué contre le paludisme Pending WO2025116843A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2023/016027 TR2023016027A2 (tr) 2023-11-29 Sıtma hastalığına karşı aseksüel kan aşamasını hedefleyen etken madde.
TR2023016027 2023-11-29

Publications (1)

Publication Number Publication Date
WO2025116843A1 true WO2025116843A1 (fr) 2025-06-05

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2024/050124 Pending WO2025116843A1 (fr) 2023-11-29 2024-02-16 Substance active ciblant le stade sanguin asexué contre le paludisme

Country Status (1)

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WO (1) WO2025116843A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006016548A1 (fr) * 2004-08-09 2006-02-16 Eisai R & D Management Co., Ltd. Agent antipaludique innovant contenant un compose hétérocyclique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006016548A1 (fr) * 2004-08-09 2006-02-16 Eisai R & D Management Co., Ltd. Agent antipaludique innovant contenant un compose hétérocyclique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BELETE TAFERE MULAW: "Recent Progress in the Development of New Antimalarial Drugs with Novel Targets", DRUG DESIGN, DEVELOPMENT AND THERAPY, DOVE MEDICAL PRESS LTD., UNITED KINGDOM, vol. Volume 14, United Kingdom , pages 3875 - 3889, XP093333896, ISSN: 1177-8881, DOI: 10.2147/DDDT.S265602 *
TRIPATHY SATYAJIT, ROY SOMENATH: "A review of age-old antimalarial drug to combat malaria: efficacy up-gradation by nanotechnology based drug delivery", ASIAN PACIFIC JOURNAL OF TROPICAL MEDICINE, HAINAN MEDICAL COLLEGE, SINGAPORE, vol. 7, no. 9, 1 September 2014 (2014-09-01), Singapore , pages 673 - 679, XP093333895, ISSN: 1995-7645, DOI: 10.1016/S1995-7645(14)60115-2 *

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