WO2012137224A1 - Coumarin compounds for the treatment of mycobacterial infections - Google Patents
Coumarin compounds for the treatment of mycobacterial infections Download PDFInfo
- Publication number
- WO2012137224A1 WO2012137224A1 PCT/IN2012/000242 IN2012000242W WO2012137224A1 WO 2012137224 A1 WO2012137224 A1 WO 2012137224A1 IN 2012000242 W IN2012000242 W IN 2012000242W WO 2012137224 A1 WO2012137224 A1 WO 2012137224A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methylcoumarin
- alkyl
- compound
- formula
- acetoxy
- 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.)
- Ceased
Links
Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
Definitions
- the present disclosure relates to the use of coumarin compounds for the treatment of mycobacterial infections and specifically to the use of coumarins for the treatment of tuberculosis.
- Tuberculosis or TB is a common and often deadly infectious disease caused by mycobacteria, usually found in humans as Mycobacterium tuberculosis. Most infections in humans result in an asymptomatic, latent infection, and about one in ten latent infections eventually progresses to active disease, which if left untreated, kills more than 50% of its victims. One third of the world's population is infected with M. tuberculosis and new infections occur at a rate of about one per second. Drug therapy is the cornerstone of TB management.
- Some of the drugs currently used for the treatment of tuberculosis are Isoniazid, Rifampicin, Ethambutol, Ethionamide, Streptomycin, Capreomycin, D- cycloserine, p-Aminosalicyclic acid, Thiacetazone, Kanamycin A, B and C.
- MDR multi drug-resistant
- the standard TB therapy is ineffective in controlling MDR- TB in high MDR-TB incidence areas.
- Fifty million people have already been infected with drug-resistant TB.
- There is much concern that the TB situation may become even worse with the spread of HIV worldwide, a virus that weakens the host immune system and allows latent TB to reactivate and makes the person more susceptible to re-infection with either drug-susceptible or drug resistant strains.
- the lethal combination of drug-resistant TB and HIV infection is a growing problem that presents serious challenges for effective TB control.
- Coumarins comprise a group of natural compounds found in a variety of plant sources. They display an extraordinary range of biochemical and pharmacological activities. Coumarins are known to function as antioxidants and enzyme inhibitors. In addition, these compounds are involved in the action of plant growth hormones and growth regulators, the control of respiration, photosynthesis, as well as defense against infections. Coumarins have long been recognized to possess anti-inflammatory, antioxidant, antiallergic, hepatoprotective, antithrombotic, antiviral, and anti-carcinogenic activities. The hydroxycoumarins are typical phenolic compounds and, therefore, act as potent metal chelators and free radical scavengers. They are powerful chain-breaking antioxidants. The coumarins display a remarkable array of biochemical and pharmacological actions, some of which suggest that certain members of this group of compounds may significantly affect the function of various mammalian cellular systems.
- Ostruthin (6-geranyl-7-hydroxycoumarin) which was isolated from the roots of Peucedanum ostruhium Koch was shown to have pronounced in vitro activity against several species of rapidly growing mycobacteria, namely Mycobacterium abscesus, M. aurum, M. fotuitum, M. phlei and M. smegmatis.
- the current therapy requires six months to treat the disease which is too long, and the treatment often has significant toxicity. These factors make patient compliance to therapy very difficult, and this noncompliance frequently selects for drug-resistant TB bacteria.
- the current TB problem clearly demonstrates the need for a re-evaluation of our knowledge of the current TB drugs and chemotherapy and the need for new and better drugs that are not only active against drug-resistant TB but also, more importantly, shorten the requirement for six months of therapy.
- the principal object of the present invention is to provide the use of the compound of formula I for the treatment of mycobacterial infection.
- Another object of the present invention is to provide use of the compound of formula I for the treatment of tuberculosis. Still another object of the present invention is to provide use of the compound of formula I for the treatment of mycobacterial infection which helps in reducing the dose as well as consequent side effects of the standard drugs without compromising on efficacy if these new molecules are incorporated into the standard treatment regimen.
- the present invention relates to method for treating mycobacterial infection/disease comprising administration of a therapeutically effective amount of compound of formula I
- T represents O; S; N j ; Ri, R 2
- X represents O, S, NR 3
- Y-Z represent Re 7 or
- Ri, R 2 can independently be H, alkyl, (CH 2 ) n aryl
- M can be O, S
- R 3 can independently be H, alkyl, (CH 2 ) n aryl, (CH 2 ) n COOH, (CH 2 ) n COOalkyl, (CH 2 ) n CONH 2 , (CH 2 ) n OH, (CH 2 ) n SH, (CH 2 ) n CONHalkyl, (CH 2 ) n CON(alkyl) 2 , (CH 2 ) n COOaryl, (CH 2 ) n CSOH, (CH 2 ) n COSH, (CH 2 ) n " CSOalkyl, (CH 2 ) preferenceCOSalkyl, (CH 2 ) n COSaryl, (CH 2 ) n CSOaryl, (CH 2 ) n haIogen, (CH 2 ) n NH 2 , (CH 2 ) n NHalkyl, (CH 2 ) n N(alkyl) 2;
- R4 - R 9 can independently be H, alkyl, (CH 2 ) n aryl, (CH 2 ) n COOH, (CH 2 ) n COOalkyl, (CH 2 ) n COOaryl, (CH 2 ) n NH 2 , (CH 2 ) n NH(alkyl), (CH 2 ) administratN(alkyl) 2 , (CH 2 ) n CONH 2 , (CH 2 ) administratCONHalkyl, (CH 2 ) n N(alkyl) 2 , (CH 2 ) n CSOH, (CH 2 ) n COSH, (CH 2 ) n CSOalkyl, (CH 2 ) dislikeCOSalkyl, (CH 2 ) n COSaryl, (CH 2 ) n CSOaryl, (CH 2 ) n CON(alkyl) 2 , (CH 2 ) n halogen,
- Rio - Ri3 can independently be H, (CH 2 ) n halogen, alkyl, (CH 2 ) favoraryl, (CH 2 ) n OH, (CH 2 ) complicatSH, (CH 2 ) n Oalkyl, (CH 2 ) n Salkyl, (CH 2 ) n NH 2 , (CH 2 ) n NHalkyl, (CH 2 ) n N(alkyl) 2 , (CH 2 ) n N0 2, (CH 2 ) n COOH, (CH 2 ) n COOalkyl, (CH 2 ) n COOaryl, (CH 2 ) distractCSOH,
- A can be 0,S, NR,
- n can be 0-10
- the present invention further relates to the use of the compound of general formula I for the treatment of mycobacterial infection and use of the same or a pharmaceutically acceptable optical and geometrical isomer or salt thereof, for the manufacture of a medicament for treating the mycobacterial infection.
- Figure 1 illustrates transmission electron micrographs of Mycobacterium tuberculosis showing cell wall lysis after treatment with polyphenolic acetates (PA).
- Figure 1(a) shows Normal cell with intact cell wall and
- Figure 2(a) shows Cell wall disrupted at lower concentrations of PA.
- Figure 2 illustrates Scanning electron micrographs of Mycobacterium tuberculosis treated with PA.
- Figure 2(a) shows Normal Cells and
- Figure 2(b) shows Cell wall showing indentation after treatment with PA.
- the inventors of the present invention have screened coumarins for their ability to inhibit the growth of Mycobacterium tuberculosis.
- the following compound of formula I was found to exhibit anti-tubercular activity.
- T represents O; S; NRi ; Ri, R 2
- X represents O, S, NR 3
- Y-Z represent ⁇ 6 R 7 or
- Ri, R 2 can independently be H, alkyl, (CH 2 ) n aryl
- M can be O, S
- R 3 can independently be H, alkyl, (CH 2 ) n aryl, (CH 2 ) deliberatelyCOOH, (CH 2 ) n COOalkyl, (CH 2 ) n CONH 2 , (CH 2 ) n OH, (CH 2 ) n SH, (CH 2 ) n CONHalkyl, (CH 2 ) n CON(alkyl) 2 , (CH 2 ) n COOaryl, (CH 2 ) n CSOH, (CH 2 ) n COSH, (CH 2 ) n CSOalkyl, (CH 2 ) n COSalkyl, (CH 2 ) n COSaryl, (CH 2 ) n CSOaryl, (CH 2 ) n halogen, (CH 2 ) n NH 2 , (CH 2 ) n NHalkyl, (CH 2 ) n N(alkyl) 2;
- R4 - R 9 can independently be H, alkyl, (CH 2 ) n aryl, (CH 2 ) n COOH, (CH 2 ) n COOalkyl, (CH 2 ) obligeCOOaryl, (CH 2 ) n NH 2 , (CH 2 ) n NH(alkyl), (CH 2 ) n N(alkyl) 2 , (CH 2 ) n CONH 2 , (CH 2 ) n CONHalkyl, (CH 2 ) n N(alkyl) 2 , (CH 2 ) n CSOH, (CH 2 ) n COSH, (CH 2 ) n CSOalkyl, (CH 2 ) n COSalkyl, (CH 2 ) n COSaryl, (CH 2 ) deliberatelyCSOaryl, (CH 2 ) dislikeCON(alkyl) 2 , (CH 2 ) conflicthalogen,
- R A, A— (CH 2 ) N - Rio - Ri 3 can independently be H, (CH 2 ) n halogen, alkyl, (CH 2 ) n aryl, (CH 2 ) deliberatelyOH, (CH 2 ) n SH, (CH 2 ) n Oalkyl, (CH 2 ) n Salkyl, (CH 2 ) n NH 2 , (CH 2 ) administratNHalkyl, (CH 2 ) n N(alkyl) 2 , (CH 2 ) n N0 2, (CH 2 ) n COOH, (CH 2 ) n COOalkyl, (CH 2 ) n COOaryl, (CH 2 ) n CSOH, (CH 2 ) preferenceCOSH, (CH 2 ) n CSOalkyl, (CH 2 ) n COSalkyl, (CH 2 ) n CSOaryl, (CH 2 ) n COSaryl,
- A can be 0,S, NR,
- n can be 0- 10
- TAase Transacetylase
- Electron microscopic pictures at sub-MIC values also show that these compounds have characteristic cell wall attacking properties.
- the above mentioned compounds were found to have good anti-mycobacterial activity which is shown both by the MIC values of the compounds as well as the electron microscopic pictures of the cells treated with the test compounds.
- polyphenols are known to have antioxidant, anti-inflammatory, anti-allergic, anti-thrombosis activity, so they have good potential for being effective anti-mycobacterial drugs because of their less cytotoxic effects.
- acylated aminocoumarins were found to be the most effective (Tables 1 and 2).
- the compounds of the instant invention are good anti-tubercular drugs. These compounds have been observed to have significant synergy with the presently available anti tuberculosis drugs. In the case of isoniazid (INH) for example, the MIC of INH reduces to one-twelfth when tested in combination with the compounds of the instant invention. These compounds show a potential to reduce the dosage of the known drugs, some of which are toxic.
- INH isoniazid
- Organism and Growth Conditions The axenic cultures of M. tuberculosis H 37 R V were cultivated in Middlebrook's 7H9 medium. The media was prepared according to the manufacturer's instructions. Compound Screening by Microplate Alamar Blue Assay (MABA)
- the compounds were first screened on H3 7 R V and then on the clinical strain 3426 using 96- well U-bottom plates. In the outer peripheral wells of the plate, 200 ⁇ of autoclaved distilled water was added to prevent evaporation of media from the inner wells. The compounds were dissolved in DMSO and further dilutions were prepared in 7H9 media. Preliminary screening involved checking the effect of compounds in a broader range of concentration from 1 to 80 ⁇ g/ml and then on the basis of the observed MIC, the drug concentrations were further narrowed down. The basic procedure involved adding of the required amount of media as well as the calculated amount of drug in each well in such a manner so that the total reaction volume was 200 ⁇ (including the inoculum).
- Controls containing no antibiotic and sterility controls without inoculation were also included.
- Single cells of MTB were prepared by filtering mid-log phase culture of MTB through 8 micron filters. The O.D. 6 oo was taken and the cell density was calculated, 10 6 cells were then added into each well except the sterility control wells. The plates were then sealed with parafilm and kept in a plastic bag. They were then kept at 37 °C. After 10 days of incubation, in case of MTB, 30 ⁇ of 0.02 % resazurin solution was added to each well, incubated overnight at 37 °C, and assessed for color development. A color change from blue to pink was considered as growth while no color change was considered as no growth. The MIC value was taken as the lowest concentration giving no color change. Similar procedure was followed for the clinical strain 3426 also.
- the culture was grown in the presence and absence of the screened compounds at sub lethal dose and was incubated for 12 days at 37 °C.
- the cells were pelleted down at 10,000 rpm and washed three times with PBS to remove media and were subsequently fixed in 1 ml fixative and kept at 4 °C.
- the electron microscopy was done at Sophisticated Analytical Instrumentation Facility (SAIF), Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to method for treating mycobacterial infection/disease by administration of a therapeutically effective amount of compound of formula I.
Description
"COUMARIN COMPOUNDS FOR THE TREATMENT OF MYCOBACTERIAL INFECTIONS" TECHNICAL FIELD
The present disclosure relates to the use of coumarin compounds for the treatment of mycobacterial infections and specifically to the use of coumarins for the treatment of tuberculosis.
BACKGROUND
Tuberculosis or TB is a common and often deadly infectious disease caused by mycobacteria, usually found in humans as Mycobacterium tuberculosis. Most infections in humans result in an asymptomatic, latent infection, and about one in ten latent infections eventually progresses to active disease, which if left untreated, kills more than 50% of its victims. One third of the world's population is infected with M. tuberculosis and new infections occur at a rate of about one per second. Drug therapy is the cornerstone of TB management. Some of the drugs currently used for the treatment of tuberculosis are Isoniazid, Rifampicin, Ethambutol, Ethionamide, Streptomycin, Capreomycin, D- cycloserine, p-Aminosalicyclic acid, Thiacetazone, Kanamycin A, B and C.
The increasing emergence of the drug-resistant TB, especially multi drug-resistant (MDR) TB is particularly alarming. The standard TB therapy is ineffective in controlling MDR- TB in high MDR-TB incidence areas. Fifty million people have already been infected with drug-resistant TB. There is much concern that the TB situation may become even worse with the spread of HIV worldwide, a virus that weakens the host immune system and allows latent TB to reactivate and makes the person more susceptible to re-infection with either drug-susceptible or drug resistant strains. The lethal combination of drug-resistant TB and HIV infection is a growing problem that presents serious challenges for effective TB control.
Coumarins comprise a group of natural compounds found in a variety of plant sources. They display an extraordinary range of biochemical and pharmacological activities.
Coumarins are known to function as antioxidants and enzyme inhibitors. In addition, these compounds are involved in the action of plant growth hormones and growth regulators, the control of respiration, photosynthesis, as well as defense against infections. Coumarins have long been recognized to possess anti-inflammatory, antioxidant, antiallergic, hepatoprotective, antithrombotic, antiviral, and anti-carcinogenic activities. The hydroxycoumarins are typical phenolic compounds and, therefore, act as potent metal chelators and free radical scavengers. They are powerful chain-breaking antioxidants. The coumarins display a remarkable array of biochemical and pharmacological actions, some of which suggest that certain members of this group of compounds may significantly affect the function of various mammalian cellular systems.
Ostruthin (6-geranyl-7-hydroxycoumarin) which was isolated from the roots of Peucedanum ostruhium Koch was shown to have pronounced in vitro activity against several species of rapidly growing mycobacteria, namely Mycobacterium abscesus, M. aurum, M. fotuitum, M. phlei and M. smegmatis.
The current therapy requires six months to treat the disease which is too long, and the treatment often has significant toxicity. These factors make patient compliance to therapy very difficult, and this noncompliance frequently selects for drug-resistant TB bacteria. The current TB problem clearly demonstrates the need for a re-evaluation of our knowledge of the current TB drugs and chemotherapy and the need for new and better drugs that are not only active against drug-resistant TB but also, more importantly, shorten the requirement for six months of therapy. OBJECT AND SUMMARY
The principal object of the present invention is to provide the use of the compound of formula I for the treatment of mycobacterial infection.
Another object of the present invention is to provide use of the compound of formula I for the treatment of tuberculosis.
Still another object of the present invention is to provide use of the compound of formula I for the treatment of mycobacterial infection which helps in reducing the dose as well as consequent side effects of the standard drugs without compromising on efficacy if these new molecules are incorporated into the standard treatment regimen.
The present invention relates to method for treating mycobacterial infection/disease comprising administration of a therapeutically effective amount of compound of formula I
T represents O; S; N j ; Ri, R2
X represents O, S, NR3
C-C
Y-Z represent Re 7 or
R8 R9
C=C or
c≡c
Ri, R2 can independently be H, alkyl, (CH2)naryl
M can be O, S
R3 can independently be H, alkyl, (CH2)naryl, (CH2)nCOOH, (CH2)nCOOalkyl, (CH2)nCONH2, (CH2)nOH, (CH2)nSH, (CH2)nCONHalkyl, (CH2)nCON(alkyl)2, (CH2)nCOOaryl, (CH2)nCSOH, (CH2)nCOSH, (CH2)n "CSOalkyl, (CH2)„COSalkyl, (CH2)nCOSaryl, (CH2)nCSOaryl, (CH2)nhaIogen, (CH2)nNH2, (CH2)nNHalkyl, (CH2)nN(alkyl)2;
R4 - R9 can independently be H, alkyl, (CH2)naryl, (CH2)nCOOH, (CH2)nCOOalkyl, (CH2)nCOOaryl, (CH2)nNH2, (CH2)nNH(alkyl), (CH2)„N(alkyl)2, (CH2)nCONH2, (CH2)„CONHalkyl, (CH2)nN(alkyl)2, (CH2)nCSOH, (CH2)nCOSH, (CH2)n CSOalkyl,
(CH2)„COSalkyl, (CH2)nCOSaryl, (CH2)nCSOaryl, (CH2)nCON(alkyl)2, (CH2)nhalogen,
Rio - Ri3 can independently be H, (CH2)nhalogen, alkyl, (CH2)„aryl, (CH2)nOH, (CH2)„SH, (CH2)nOalkyl, (CH2)nSalkyl, (CH2)nNH2, (CH2)nNHalkyl, (CH2)nN(alkyl)2, (CH2)nN02, (CH2)nCOOH, (CH2)n COOalkyl, (CH2)nCOOaryl, (CH2)„CSOH,
,
A can be 0,S, NR,
n can be 0-10
including pharmaceutically acceptable optical and geometrical isomers or salts
The present invention further relates to the use of the compound of general formula I for the treatment of mycobacterial infection and use of the same or a pharmaceutically acceptable optical and geometrical isomer or salt thereof, for the manufacture of a medicament for treating the mycobacterial infection.
BRIEF DESCRIPTION OF DRAWINGS
The aforementioned aspects and other features of the present disclosure will be explained in the following description, taken in conjunction with the accompanying drawing, wherein:
Figure 1 illustrates transmission electron micrographs of Mycobacterium tuberculosis showing cell wall lysis after treatment with polyphenolic acetates (PA). Figure 1(a) shows Normal cell with intact cell wall and Figure 2(a) shows Cell wall disrupted at lower concentrations of PA.
Figure 2 illustrates Scanning electron micrographs of Mycobacterium tuberculosis treated with PA. Figure 2(a) shows Normal Cells and Figure 2(b) shows Cell wall showing indentation after treatment with PA. While the disclosure will be described in conjunction with the illustrated embodiment, it will be understood that it is not intended to limit the disclosure to such embodiment. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the spirit and scope of the disclosure as defined by the appended claims.
DETAILED DESCRIPTION
The embodiments of the present disclosure will now be described in detail with reference to the accompanying examples. However, the present disclosure is not limited to the embodiments. The present disclosure can be modified in various forms. Thus, the embodiments of the present disclosure are only provided to explain more clearly the present disclosure to the ordinarily skilled in the art of the present disclosure.
The inventors of the present invention have screened coumarins for their ability to inhibit the growth of Mycobacterium tuberculosis. The following compound of formula I was found to exhibit anti-tubercular activity.
I
wherein:
T represents O; S; NRi ; Ri, R2
X represents O, S, NR3
C-C
Y-Z represent ^6 R7 or
Re ¾
C=C or
c≡c
Ri, R2 can independently be H, alkyl, (CH2)naryl
M can be O, S
R3 can independently be H, alkyl, (CH2)naryl, (CH2)„COOH, (CH2)nCOOalkyl, (CH2)nCONH2, (CH2)nOH, (CH2)nSH, (CH2)nCONHalkyl, (CH2)nCON(alkyl)2, (CH2)nCOOaryl, (CH2)nCSOH, (CH2)nCOSH, (CH2)n CSOalkyl, (CH2)nCOSalkyl, (CH2)nCOSaryl, (CH2)nCSOaryl, (CH2)nhalogen, (CH2)nNH2, (CH2)nNHalkyl, (CH2)nN(alkyl)2;
R4 - R9 can independently be H, alkyl, (CH2)naryl, (CH2)nCOOH, (CH2)nCOOalkyl, (CH2)„COOaryl, (CH2)nNH2, (CH2)nNH(alkyl), (CH2)nN(alkyl)2, (CH2)nCONH2, (CH2)nCONHalkyl, (CH2)nN(alkyl)2, (CH2)nCSOH, (CH2)nCOSH, (CH2)n CSOalkyl, (CH2)nCOSalkyl, (CH2)nCOSaryl, (CH2)„CSOaryl, (CH2)„CON(alkyl)2, (CH2)„halogen,
M
R A, A— (CH2)N- Rio - Ri3 can independently be H, (CH2)nhalogen, alkyl, (CH2)naryl, (CH2)„OH, (CH2)nSH, (CH2)nOalkyl, (CH2)nSalkyl, (CH2)nNH2, (CH2)„NHalkyl, (CH2)nN(alkyl)2, (CH2)nN02, (CH2)nCOOH, (CH2)n COOalkyl, (CH2)nCOOaryl, (CH2)nCSOH, (CH2)„COSH, (CH2)nCSOalkyl, (CH2)nCOSalkyl, (CH2)nCSOaryl, (CH2)nCOSaryl,
A can be 0,S, NR,
n can be 0- 10
including pharmaceutically acceptable optical and geometrical isomers or salts
The following compounds in particular were found to be effective in inhibiting the growth of Mycobacterium tuberculosis.
7,8-diacetoxy-4-methylcoumarin (1)
7,8-dihydroxy-4-methyIcoumarin (2)
7,8-diacetoxy-3-(2-ethoxycarbonylethyl)-4-methylcoumarin (3)
4-methyl-7-thioacetoxycoumarin (4)
7,8-dipropanoyloxy-4-methylcoumarin (5)
7-acetoxy-4-methylcoumarin (6)
7,8-dibutanoyloxy-4-methylcoumarin (7)
7,8-diacetoxy-5-carboxy-4-methylcoumarin (8)
7,8-diacetoxy-3-hexyl-4-methylcoumarin (9)
7,8-dipropanoyloxy-6-carboxy-4-methylcoumarin (10)
7,8-diacetoxy-3-decyl-4-methylcoumarin (11)
7-acetoxy-3-decyl-4-methylcoumarin (12)
7-hydroxy-6-carboxy-4-methylcoumarin (13)
7-amino-4-methylcoumarin (14)
7-propanoylamino-4-methylcoumarin (15)
7-butanoylamino-4-methylcoumarin (16)
7-pentanoylamino-4-methylcoumarin (17)
7-hexanoylamino-4-methylcoumarin (18)
7-benzoylamino-4-methylcoumarin (19)
7-acetoxy-4-methylquinolone (20)
7-acetoxy-3-ethyl-4-methylquinolone (21)
7-acetoxy-3-hexyl-4-methylquinolone (22)
6- acetoxy-4-methylquinolone (23)
7- acetoxy-l-ethylethanoate-4- methylquinolone (24)
It was found that the enzyme "Acetoxydrug: Transacetylase (TAase)" in the liver microsomes can transfer acetyl group from DAMC to the protein (P-450). This novel enzyme has been purified from rat liver and human placenta. It is also present in various other eukaryotic sources. So the inventors were interested to explore the presence of protein transacetylase in the mycobacteria.
Electron microscopic pictures at sub-MIC values also show that these compounds have characteristic cell wall attacking properties.
The above mentioned compounds were found to have good anti-mycobacterial activity which is shown both by the MIC values of the compounds as well as the electron microscopic pictures of the cells treated with the test compounds. Since polyphenols are known to have antioxidant, anti-inflammatory, anti-allergic, anti-thrombosis activity, so they have good potential for being effective anti-mycobacterial drugs because of their less cytotoxic effects. Out of all these compounds, acylated aminocoumarins were found to be the most effective (Tables 1 and 2).
Table 1: MIC values of compounds against M. tuberculosis
7-amino-4-methylcoumarin (14) 1
7-propanoylamino-4-methylcoumarin (15) 3
7-butanoylamino-4-methylcoumarin (16) 2
7-pentanoy lam ino-4-methy lcoumarin (17) 2
7-hexanoylamino-4-methylcoumarin (18) 2
7-benzoylamino-4-methylcoumarin (19) >80
7-acetoxy-4-methylquinolone (20) 5-7
7-acetoxy-3-ethyl-4-methylquinolone (21) 10-20
7-acetoxy-3-hexyl-4-methylquinolone (22) 4
6-acetoxy-4-methylquinolone (23) > 20
7-acetoxy-l-ethylethanoate-4-methylquinolone >20
(24)
Table 2; MIC values of compounds against clinical isolate 3426
Investigations have also suggested that these aminocoumarins may work in synergy with standard first line drugs (Table 3). This may help in reducing the dose as well as consequent side effects of the standard drugs without compromising on efficacy if these
new molecules are incorporated into the standard treatment regimen. Compound 14 found to be the most effective compound of all as shown by its M IC value.
Table 3; Combination studies of our compounds with Isoniazid (INH).
MIC of INH as reported in literature = 0.025 - 0.2 /ml
MIC of INH on H37RV under our experimental conditions = 0.03 /mI
The compounds of the instant invention are good anti-tubercular drugs. These compounds have been observed to have significant synergy with the presently available anti tuberculosis drugs. In the case of isoniazid (INH) for example, the MIC of INH reduces to one-twelfth when tested in combination with the compounds of the instant invention. These compounds show a potential to reduce the dosage of the known drugs, some of which are toxic.
Organism and Growth Conditions
The axenic cultures of M. tuberculosis H37RV were cultivated in Middlebrook's 7H9 medium. The media was prepared according to the manufacturer's instructions. Compound Screening by Microplate Alamar Blue Assay (MABA)
The compounds were first screened on H37RV and then on the clinical strain 3426 using 96- well U-bottom plates. In the outer peripheral wells of the plate, 200 μΐ of autoclaved distilled water was added to prevent evaporation of media from the inner wells. The compounds were dissolved in DMSO and further dilutions were prepared in 7H9 media. Preliminary screening involved checking the effect of compounds in a broader range of concentration from 1 to 80 μg/ml and then on the basis of the observed MIC, the drug concentrations were further narrowed down. The basic procedure involved adding of the required amount of media as well as the calculated amount of drug in each well in such a manner so that the total reaction volume was 200 μΐ (including the inoculum). Controls containing no antibiotic and sterility controls without inoculation were also included. Single cells of MTB were prepared by filtering mid-log phase culture of MTB through 8 micron filters. The O.D.6oo was taken and the cell density was calculated, 106 cells were then added into each well except the sterility control wells. The plates were then sealed with parafilm and kept in a plastic bag. They were then kept at 37 °C. After 10 days of incubation, in case of MTB, 30 μΐ of 0.02 % resazurin solution was added to each well, incubated overnight at 37 °C, and assessed for color development. A color change from blue to pink was considered as growth while no color change was considered as no growth. The MIC value was taken as the lowest concentration giving no color change. Similar procedure was followed for the clinical strain 3426 also.
Combination studies with standard drugs and test compounds
Combination studies were also done using the Alamar Blue assay. H37RV was tested for susceptibility and MIC with different concentrations of the compounds and standard drugs which are used in TB therapy.
Initially, the concentration of the standard drug was kept constant and that of the test compound was varied. However, it was taken care that both the concentrations, i.e. of the
standard drug as well as of the test compound were lower than their actual MIC values. In other words, it can be said that a sub-inhibitory concentration of standard drug was chosen and it was put in combination with different concentrations (sub-inhibitory) of the compounds of the instant invention to see the resultant effect on the bacterial growth. The Fractional Inhibitory Concentration (FIC) was then calculated. Fractional Inhibitory Concentration indices are designated as follows:
> 2 antagonistic,
<0.5 synergistic,
>0.5-< 1.0 additive,
>1.0-< 2.0 indifferent.
Electron Microscopy with sub lethal dose
The culture was grown in the presence and absence of the screened compounds at sub lethal dose and was incubated for 12 days at 37 °C. The cells were pelleted down at 10,000 rpm and washed three times with PBS to remove media and were subsequently fixed in 1 ml fixative and kept at 4 °C. The electron microscopy was done at Sophisticated Analytical Instrumentation Facility (SAIF), Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi.
Although the disclosure of system and method has been described in connection with the embodiment of the present disclosure illustrated in the accompanying drawings, it is not limited thereto. It will be apparent to those skilled in the art that various substitutions, modifications and changes may be made thereto without departing from the scope and spirit of the disclosure.
The various embodiments described above can be combined to provide further embodiments. All of the non-patent publications referred to in this specification are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.
These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to
limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.
Examples: Synthesis of Aminocoumarins and their Acylates Synthesis of 7-amino-4-methy!coumarin (14)
The synthesis of 7-amino-4-methylcoumarin (14) was achieved starting from m- aminophenol. Ethyl chloroformate (l eq.) was added to a stirred suspension of m- aminophenol (5.0 g, 45.8 mmol) in 200 ml dry diethyl ether at 0 °C. A white precipitate (the amine hydrochloride) formed immediately. The reaction mixture was stirred for an additional 2 h at room temperature. The product formation was monitored by TLC. The hydrochloride was removed by filtration. Evaporation of solvent gives grey solid. The crystallization of the crude product from benzene-cyclohexane (200/400 ml) at 0 °C gave pure protected aminophenol as colourless solid in 84.0 % yield. M.P.: 94-95 °C (lit. 94-95 °C). The colourless solid so obtained and ethyl acetoacetate (1.2 eq.) was stirred at 0 °C followed by dropwise addition of 70 % H2S04 in ethanol. The reaction mixture was stirred for 4 h at room temperature and the product formation was monitored by TLC. The clear yellow solution was poured in 400 ml of ice water, giving a white crystalline ppt. The solid filtered and crystallized from absolute ethanol to give colourless needle of pure protected aminocoumarin in 83.0 % yield. M.P.: 187-189 °C (lit.186-188 °C). 7- Carbethoxyamino-4-methylcoumarin so obtained was heated at reflux for 4 h at 120 °C in concentrated sulphuric acid using glacial acetic acid as solvent. The progress of the reaction was monitored on TLC. On cooling, a yellow precipitate was obtained. The mixture was poured into 200 ml of ice-cold water and let to stand overnight. The resulting suspension was made slightly basic with 50 % NaOH with cooling by addition of ice chips. The yellow precipitate was filtered and washed with ice water. The crude product was crystallized from ethanol to give yellow needles of pure 7-amino-4-methylcoumarin (15) in 99.0 % yield (Scheme 1). M.P.: 218-22 °C (lit. 220-224 °C). IR (KBr) vmax: 3439 (NH), 3355 (NH), 3246 (CH), 1696 (CO lactone), 1544, 1397, 1062 and 831 cm'1; Ή NMR (300 MHz, OMSO-d6): 6 2.28 (3H, s, C-4CH3), 5.88 (1Η, s, -NH), 6.09 (2Η, brs, NH and C-3H), 6.39-6.55 (2Η, m, aromatic protons) and 7.38 (1Η, s, aromatic proton).
13C NMR (75.5 MHz, DMSO-i¾: δ 18.57 (C-4CH3), 99.06, 108.01, 109.39, 1 1 1.71 , 126.75, 153.62, 154.30 and 156.00 (aromatic carbons) and 161.29 (CO); HRMS (ESI positive mode): m/z 176.0701 [M+H]+, calculated for C,oH9N02+H 176.0706.
15 = -COCH2CH3
16 R = -COCH2CH2CH3
17 R = -COCH2CH2CH2CH3
18 R = -COCH2CH2CH2CH2CH3
SCHEME-1
General procedure for synthesis of substituted 7-acylamino-4-methylcoumarins (15- 18): To a solution of 7-amino-4-methylcoumarin (1.0 g, 5.71 mmol) in pyridine (15 ml) acid anhydride, i.e. propanoic anhydride / butanoic anhydride / pentanoic anhydride / hexanoic anhydride (1.3 eq) was added followed by the addition of a pinch of DMAP (20 mg). The reaction mixture was incubated in shaker at 60 °C and the progress of reaction was monitored on TLC. On completion of reaction, 10 % dilute hydrochloric acid (100 ml) was added into it to neutralize the reaction mixture. The separated solid was then filtered, washed with water and dried under vacuum. The crude solid product was recrystallized from ethanol to afford 7-propanoylamino-4-methylcoumarin (15), 7-butanoylamino-4- methylcoumarin (16), 7-pentanoylamino-4-methylcoumarin (17) and 7-hexanoylamino-4- methylcoumarin (18) in 81.6 to 90.9 % yield.
7-Propanoylamino-4-methylcoumarin (15)
It was obtained as white solid in 90.9 % yield; M.P. 230-238 °C; IR (KBr) vmax: 3295 (NH), 2980, 1688 (lactone CO), 1620 (amidic CO), 1586, 1401 , 1223 and 844 cm"'; Ή NMR (300 MHz, DMSO-c¾): δ 1.07 (3H, t, J = 7.5 Hz, -COCH3CH3), 2.32-2.40 (5Η, m, - COCH2CH3 and C-4CH3), 6.23 (1 Η, s, C-3H), 7.45 (1 Η, dd, J = 8.7 and 1 .8 Hz, aromatic proton), 7.67 (1 H, d, J = 8.7 Hz, aromatic proton), 7.74 (1 H, d, J = 1.8 Hz, aromatic proton) and 10.28 (1 H, s, -NH); 13C NMR (75.5 MHz, OMSO-d6): δ 9.32 (-COCH2CH3), 17.92 (C-4CH3), 29.60 (-COCH2CH3), 105.33, 1 12.03, 1 14.69, 1 14.97, 125.82, 142.65, 153.08 and 153.66 (aromatic carbons), 160.03 (CO, lactone) and 172.71 (CO, amide); HRMS (ESI positive mode): m/z 254.0728 [M+Na]+, calculated for Cl 3Hi3N03+Na 254.0788.
7-Butanoylamino-4-methylcoumarin (16)
It was obtained as white solid in 85.7 % yield. M.P.: 205-208 °C; IR (KBr) vmax: 3293(NH), 2960, 1688 (CO lactone), 1621 (CO amidic), 1586, 1402, 1 185 and 845 cm"1; Ή NMR (300 MHz, DMSO-i¾): δ 0.90 (3H, t, J = 7.2 Hz, -COCH2CH2CH3), 1.61 (2Η, sext, J = 7.2 Hz, -COCH2CH2CH3), 2.30-2.37 (5H, m, -COCH2CH2CH3 and C-4CH3), 6.22 (1Η, s, C-3H), 7.45 (1Η, dd, J = 8.5 and 1.8 Hz, aromatic proton), 7.67 (1 H, d, J = 8.4 Hz, aromatic proton), 7.74 (l H, d, J = 1.8 Hz, aromatic proton) and 10.28 (1H, s, - NH); 13C NMR (75.5 MHz, DMSO-tf6): 5 13.55 (-COCH2CH2CH3), 18.30 (- COCH2CH2CH3), 17.92 (C-4CH3), 38.39 (-COCH2CH2CH3), 105.37, 1 12.05, 1 14.73, 1 15.00, 125.80, 142.59, 153.06 and 153.66 (aromatic carbons), 160.02 (CO, lactone) and 171.89 (CO, amide); HRMS (ESI positive mode): m/z 268.0955 [M+Na]+, calculated for C14Hi5N03+Na 268.0944. 7-PentanoyIamino-4-methylcoumarin (17)
It was obtained as white solid in 81.6 % yield. M.P. 202-206 °C; IR (KBr) vmax: 3295 (NH), 3092, 2956, 1686 (CO lactone), 1619 (CO amidic), 1587, 1405, 1 183 and 843 cm ' ; Ή NMR (300 MHz,DMSO-rfi) :6 0.88 (3H, t, J = 7.5 Hz, -COCH2CH2CH2CH3), 1.32 (2Η, sext, J = 7.5 Hz, -COCH2CH2CH2CH3), 1.57 (2H, pentet, J = 7.5Hz, - COCH2CH2CH2CH3), 2.32-2.37 (5H, m, -COCH2CH2CH2CH3 and C-4CH3), 6.22 (1 Η, s, C-3H), 7.45 (1 Η, d, J = 7.5 Hz, aromatic proton), 7.67 (1 H, d, J = 7.5 Hz, aromatic proton), 7.74 (1 H, d, J = 1.8 Hz, aromatic proton) and 10.27 (1 H, s, -NH); 13C NMR (75.5 MHz, DMSO-i¾: δ 13.67 (-COCH2CH2CH2 CH3), 17.91 (C-4CH3), 21.76 (-
COCH2CH2CH2CH3), 26.97 (COC H2CH2C H2CH3), 36.21 (COCH2C H2C H2CH3), 105.36, 1 12.05, 1 14.72, 1 14.99, 125.79, 142.60, 153.05 and 152.65 (aromatic carbons), 160.02 (CO lactone) and 172.03 (CO am ide); HRMS (ESI positive mode): m/z 259.3000 [M+H]+, calculated for Ci5H,7N03+H 259.3033.
7-hexanoylamino-4-methylcoumarin (18)
It was obtained as white solid in 81.8 % yield. M.P. 206-210°C; IR (KBr) vmax: 3425(NH), 3295, 2929 (CH), 1688 (CO lactone), 1620 (CO amidic), 1587, 1403, 1 174 and 843 cm'1 ; Ή NMR (300 MHz, DIVISOR): δ 0.86 (3H, t, J = 7.5 Hz, -COCH2CH2CH2CH2CH3), 1.28 (4Η, brs, -COCH2CH2CH2CH2CH3 and -COCH2CH2CH2CH2CH3), 1.59 (2H, brs, - COCH2CH2 CH2CH2CH3), 2.32-2.37 (5H, m, -COCH2CH2CH2CH2CH3 and C-4CH3), 6.21 (1Η, s, C-3H), 7.44 ( 1 Η, d, J= 8.1 Hz, aromatic proton), 7.66 (1H, d, J = 8.1 Hz, aromatic proton), 7.74 (1 H, s, aromatic proton) and 10.26 (1H, s, -NH); , 3C NMR (75.5 MHz, DMSO-i¾: δ 13.80 (-COCH2CH2CH2CH2CH3), 17.91 (C-4CH3), 21 .84 (COCH2CH2CH2CH2CH3), 24.52 (CO CH2CH2CH2CH2CH3), 30.82 (COCH2CH2CH2CH2CH3), 36.46 (COCH2CH2CH2CH2CH3), 105.35, 1 12.04, 1 14.72, 1 14.98 , 125.78, 142.60, 153.04 and 153.65 (aromatic carbons), 160.01 (CO, lactone) and 172.02 (CO, amide); HRMS (ESI positive mode): m/z 274.1439 [M+H]+ , calculated for
Claims
1. Method for treating Mycobacterial infection/disease comprising administration of a therapeutically effective amount of compound of formula I
I
wherein:
T represents O; S; NRt ; R|, R2
X represents O, S, NR3
C-C
Y-Z represent ¾ R7 or
R8 ^9
C=C or
c≡c
Ri, R2 can independently be H, alkyl, (CH2)naryl
M can be O, S
R3 can independently be H, alkyl, (CH2)naryl, (CH2)„COOH, (CH2)nCOOalkyl, (CH2)nCONH2, (CH2)nOH, (CH2)nSH, (CH2)„CONHalkyl, (CH2)nCON(alkyl)2, (CH2)nCOOaryl, (CH2)nCSOH, (CH2)nCOSH, (CH2)n-CSOalkyl, (CH2)nCOSalkyl, (CH2)„COSaryl, (CH2)nCSOaryl, (CH2)nhalogen, (CH2)„NH2, (CH2)nNHalkyl, (CH2)nN(alkyl)2;
R4 - R9 can independently be H, alkyl, (CH2)naryl, (CH2)nCOOH, (CH2)nCOOalkyl, (CH2)nCOOaryl, (CH2)nNH2, (CH2)nNH(alkyl), (CH2)nN(alkyl)2, (CH2)nCONH2, (CH2)nCONHalkyl, (CH2)nN(alkyl)2, (CH2)nCSOH, (CH2)„COSH,
(CH2)„CSOalkyl, (CH2)nCOSalkyl, (CH2)nCOSaryl, (CH2)nCSOaryl,
M
• (CH2)„CON(alkyl)2, (CH2)nhalogen, Ai A-<CH2)n-
Rio - Ri3 can independently be H, (CH2)nhalogen, alkyl, (CH2)naryl, (CH2)nOH, (CH2)nSH, (CH2)nOalkyl, (CH2)nSalkyl, (CH2)„NH2, (CH2)nNHalkyl, (CH2)nN(alkyl)2, (CH2)nN02, (CH2)nCOOH, (CH2)n COOalkyl, (CH2)nCOOaryl, (CH2)nCSOH, (CH2)nCOSH, (CH2)nCSOalkyl, (CH2)nCOSalkyl, (CH2)nCSOaryl, (CH2)nCOSaryl, (CH2)nCONH2, (CH2)nCONHalkyl, (CH2)„CON(alkyl)2,
A can be 0,S, NRi
n can be 0-10
including pharmaceutically acceptable optical and geometrical isomers or salts
The method as claimed in claim 1, wherein said compound of formula I
from the group consisting of the following compounds:
7,8-diacetoxy-4-methylcoumarin (1)
7,8-dihydroxy-4-methylcoumarin
(2)
7,8-diacetoxy-3-(2-ethoxycarbonylethyl)-4-methylcoumarin (3)
4-methyl-7-thioacetoxycoumarin (4)
7,8-dipropanoyloxy-4-methylcoumarin (5)
7-acetoxy-4-methylcoumarin (6)
7,8-dibutanoyloxy-4-methylcoumarin (7)
7,8-diacetoxy-5-carboxy-4-methylcoumarin (8)
7,8-diacetoxy-3-hexyl-4-methylcoumarin (9)
7,8-dipropanoyloxy-6-carboxy-4-methylcoumarin (10)
7,8-diacetoxy-3-decyl-4-methylcoumarin (11)
7-acetoxy-3-decyl-4-methylcoumarin (12)
7-hydroxy-6-carboxy-4-methylcoumarin (13)
7-amino-4-methylcoumarin (14)
7-propanoylamino-4-methylcoumarin (15)
7-butanoylamino-4-methylcoumarin (16)
7-pentanoy lamino-4-methy lcoumarin (17)
7-hexanoy lam ino-4-methy lcoumarin ( 18)
7-benzoylam ino-4-methylcoumarin (19)
7-acetoxy-4-methylquinolone (20)
7-acetoxy-3-ethyl-4-methylquinolone (21)
7-acetoxy-3-hexyl-4-methylquinolone (22)
6- acetoxy-4-methylquinolone (23)
7- acetoxy-l-ethylethanoate-4- methylquinolone (24)
3. The method as claimed in claim 1, wherein said compound of formula I is 7- amino-4-methylcoumarin.
4. The method as claimed in claim 1, wherein said compound of formula I is 7- propanoylamino-4-rnethylcournarin.
5. The method as claimed in claim 1, wherein said compound of formula I is 7- butanoylamino-4-methylcoumarin.
6. The method as claimed in claim 1, wherein said compound of formula I is 7- pentanoyIamino-4-methylcoumarin.
7. The method as claimed in claim 1, wherein said compound of formula I is 7- hexanoylamino-4-methylcoumarin.
8. The method as claimed in claim 1, wherein said compound of formula I is 7,8- diacetoxy-4-methylcoumarin.
9. The method as claimed in claim 1 , wherein said Mycobacterial infection/ disease is tuberculosis.
10. Use of the compound of general formula I in the preparation of a medicament for the treatment of Mycobacterial infection.
1 1. Use of the compound as claimed in claim 10, wherein said infection is tuberculosis.
12. Use of a compound of the general formula I or a pharmaceutically acceptable optical and geometrical isomers and salts thereof, for the manufacture of a medicament for treating Mycobacterial infection.
13. Use of a compound of the general formula I, for the preparation of a pharmaceutical composition for treating Mycobacterial infection.
14. Use of a compound of the general formula I as claimed in claim 1 in combination with a conventional anti-tubercular drug for the preparation of a pharmaceutical composition for the treatment of mycobacterial infection.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN983/DEL/2011 | 2011-04-05 | ||
| IN983DE2011 | 2011-04-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2012137224A1 true WO2012137224A1 (en) | 2012-10-11 |
Family
ID=46968684
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2012/000242 Ceased WO2012137224A1 (en) | 2011-04-05 | 2012-04-04 | Coumarin compounds for the treatment of mycobacterial infections |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2012137224A1 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104031014A (en) * | 2013-03-08 | 2014-09-10 | 华中师范大学 | Coumarin derivatives, preparation method of coumarin derivatives, and elastase activity detection method and kit |
| CN104165869A (en) * | 2013-05-17 | 2014-11-26 | 华中师范大学 | Detection method for activity of proteolytic enzyme |
| US9388161B2 (en) | 2013-11-18 | 2016-07-12 | Forma Therapeutics, Inc. | Tetrahydroquinoline compositions as BET bromodomain inhibitors |
| US10029995B2 (en) | 2015-09-03 | 2018-07-24 | Forma Therapeutics, Inc. | [6,6] fused bicyclic HDAC8 inhibitors |
| CN109020943A (en) * | 2018-08-27 | 2018-12-18 | 中国海洋大学 | A kind for the treatment of tuberculosis polyketides and its preparation method and application |
| US10377769B2 (en) | 2013-11-18 | 2019-08-13 | Forma Therapeutics, Inc. | Benzopiperazine compositions as BET bromodomain inhibitors |
| CN111925348A (en) * | 2020-07-24 | 2020-11-13 | 贵州民族大学 | Coumarin Schiff base derivative and preparation method and application thereof |
| WO2023034339A1 (en) * | 2021-08-30 | 2023-03-09 | Pretzel Therapeutics, Inc. | Hydroxy and alkoxy coumarins as modulators of polrmt |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6670383B2 (en) * | 2001-03-16 | 2003-12-30 | Advanced Life Sciences, Inc. | Pyranocoumarin compounds as a novel pharmacophore with anti-TB activity |
| WO2009157020A1 (en) * | 2008-06-23 | 2009-12-30 | Delhi University | Coumarin compounds for the treatment of cardiovascular diseases and process for preparing the same |
-
2012
- 2012-04-04 WO PCT/IN2012/000242 patent/WO2012137224A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6670383B2 (en) * | 2001-03-16 | 2003-12-30 | Advanced Life Sciences, Inc. | Pyranocoumarin compounds as a novel pharmacophore with anti-TB activity |
| WO2009157020A1 (en) * | 2008-06-23 | 2009-12-30 | Delhi University | Coumarin compounds for the treatment of cardiovascular diseases and process for preparing the same |
Non-Patent Citations (1)
| Title |
|---|
| ANANTHAN ET AL.: "High Throughput Screening for Inhibitors of Mycobacterium tuberculosis H37Rv.", TUBERCULOSIS (EDINB), vol. 89, no. 5, 2009, pages 1 - 58 334-353, XP026732373, DOI: doi:10.1016/j.tube.2009.05.008 * |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104031014B (en) * | 2013-03-08 | 2016-05-11 | 华中师范大学 | Coumarin derivative and preparation method thereof and elastase activity detection method and detection kit |
| CN104031014A (en) * | 2013-03-08 | 2014-09-10 | 华中师范大学 | Coumarin derivatives, preparation method of coumarin derivatives, and elastase activity detection method and kit |
| CN104165869A (en) * | 2013-05-17 | 2014-11-26 | 华中师范大学 | Detection method for activity of proteolytic enzyme |
| CN104165869B (en) * | 2013-05-17 | 2016-12-28 | 华中师范大学 | A kind of method detecting hydrolase of proteolysis |
| US10703764B2 (en) | 2013-11-18 | 2020-07-07 | Forma Therapeutics, Inc. | Benzopiperazine compositions as BET bromodomain inhibitors |
| US9388161B2 (en) | 2013-11-18 | 2016-07-12 | Forma Therapeutics, Inc. | Tetrahydroquinoline compositions as BET bromodomain inhibitors |
| US11111229B2 (en) | 2013-11-18 | 2021-09-07 | Forma Therapeutics, Inc. | Tetrahydroquinoline compositions as BET bromodomain inhibitors |
| US11084831B1 (en) | 2013-11-18 | 2021-08-10 | Forma Therapeutics, Inc. | Benzopiperazine compositions as BET bromodomain inhibitors |
| US10336722B2 (en) | 2013-11-18 | 2019-07-02 | Forma Therapeutics, Inc. | Tetrahydroquinoline compositions as BET bromodomain inhibitors |
| US10377769B2 (en) | 2013-11-18 | 2019-08-13 | Forma Therapeutics, Inc. | Benzopiperazine compositions as BET bromodomain inhibitors |
| US10611750B2 (en) | 2013-11-18 | 2020-04-07 | Forma Therapeutics, Inc. | Tetrahydroquinoline compositions as bet bromodomain inhibitors |
| US10370343B2 (en) | 2015-09-03 | 2019-08-06 | Forma Therapeutics, Inc. | [6,6] Fused bicyclic HDAC8 inhibitors |
| US10829460B2 (en) | 2015-09-03 | 2020-11-10 | Valo Early Discovery, Inc. | [6,6] fused bicyclic HDAC8 inhibitors |
| US10029995B2 (en) | 2015-09-03 | 2018-07-24 | Forma Therapeutics, Inc. | [6,6] fused bicyclic HDAC8 inhibitors |
| US11414392B2 (en) | 2015-09-03 | 2022-08-16 | Valo Health, Inc. | [6,6] fused bicyclic HDAC8 inhibitors |
| CN109020943A (en) * | 2018-08-27 | 2018-12-18 | 中国海洋大学 | A kind for the treatment of tuberculosis polyketides and its preparation method and application |
| CN111925348A (en) * | 2020-07-24 | 2020-11-13 | 贵州民族大学 | Coumarin Schiff base derivative and preparation method and application thereof |
| WO2023034339A1 (en) * | 2021-08-30 | 2023-03-09 | Pretzel Therapeutics, Inc. | Hydroxy and alkoxy coumarins as modulators of polrmt |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2012137224A1 (en) | Coumarin compounds for the treatment of mycobacterial infections | |
| JP5502731B2 (en) | New antimicrobial compounds, their synthesis and their use for the treatment of mammalian infections | |
| JP5068813B2 (en) | Novel benzothiazinone derivatives and their use as antibacterial agents | |
| WO2013040528A1 (en) | Antimicrobial compounds | |
| WO2013052263A2 (en) | Antifungal compounds | |
| Baranyai et al. | Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates | |
| WO2007149782A2 (en) | Selective inhibitors for transferases | |
| EA023879B1 (en) | 2-piperazin-1-yl-4h-1,3-benzothiazin-4-one derivatives and their use for the treatment of mammalian infections | |
| JP2018502845A (en) | Antimicrobial polymyxins for the treatment of bacterial infections | |
| WO2013040527A1 (en) | Antimicrobial compounds | |
| WO2013142812A1 (en) | Antibacterial agents: sidechain-fluorinated myxopyronin derivatives | |
| JP2014503601A (en) | Phenyl-isoxazole derivative and method for producing the same | |
| AU2012310242A1 (en) | Benzothiazinone derivatives as anti -tuberculosis agents | |
| Doğruer et al. | Synthesis and antimicrobial activity of some 3 (2H)-pyridazinone and 1 (2H)-phthalazinone derivatives | |
| KR20220075335A (en) | antibacterial compound | |
| KR20220071199A (en) | 4-quinolinone antibacterial compound | |
| CA2531766A1 (en) | Entry inhibitors of the hiv virus | |
| CA2325689A1 (en) | Substituted aromatic compounds for treatment of antibiotic resistant infections | |
| WO2013040526A1 (en) | Antimicrobial compounds | |
| WO2011140680A1 (en) | Urea compounds and use thereof for inhibiting apoptosis | |
| US20160221977A1 (en) | Antibacterial beta-lactones, and methods of identification, manufacture and use | |
| CN115960031A (en) | Tetrahydroisoindolone compound and preparation method and application thereof | |
| CN102453028A (en) | Antifungal agent-2- [ (2, 3-dihydro-4H-benzo [ b ] thiopyran-4-ylidene) hydrazono ] -4-oxotetrahydrothia (oxazole) -5-acetic acid derivative | |
| US20220081470A1 (en) | Thiazolyl peptides for the treatment nontuberculous mycobacterial infections | |
| JP6586692B2 (en) | Novel quinone derivatives and antitrypanosoma agents containing them as active ingredients |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12767429 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 12767429 Country of ref document: EP Kind code of ref document: A1 |