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1.
Bioorg Med Chem Lett ; 24(13): 2940-4, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24835630

RESUMO

In the present study, an efficient synthesis of some Mannich base of 5-methyl-2-[(2-oxo-2H-chromen-3-yl)carbonyl]-2,4-dihydro-3H-pyrazol-3-one (4a-j) have been described by using conventional and non-conventional (microwave) techniques. Microwave assisted reactions showed that require shorter reaction time and good yield. The newly synthesized compounds were screened for their anti-inflammatory, analgesic activity, antioxidant, and antibacterial effects were compared with standard drug. Among the compounds studied, compound (4f) showing nearly equipotent anti-inflammatory and analgesic activity than the standard drug (indomethacin), along with minimum ulcerogenic index. Compounds (4b and 4i) showing 1.06 times more active than ciprofloxacin against tested Gram-negative bacteria.


Assuntos
Analgésicos/farmacologia , Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Micro-Ondas , Pirazolonas/farmacologia , Ácido Acético , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/administração & dosagem , Antiulcerosos/química , Bactérias/efeitos dos fármacos , Carragenina/administração & dosagem , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Dor/induzido quimicamente , Dor/tratamento farmacológico , Pirazolonas/administração & dosagem , Pirazolonas/química , Ratos , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 22(14): 4807-9, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22726933

RESUMO

A series of 4-aryl/alkylsulfonylmethylcoumarins have been synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H(37)Rv (MTB). Four of the compounds showed MIC in the range of 0.78-3.13 µg/mL proving their potential activity.


Assuntos
Antituberculosos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 21(18): 5149-54, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21840711

RESUMO

Various 3-nitropropionamides were synthesized and evaluated for in vitro activities against log and starved phase culture of two mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among 22 compounds, 1-cyclopropyl-7-(3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (22) was found to be the most active compound in vitro with MICs of 0.16 and 0.04 µM against log- and starved-phase culture of MTB. Compound 22 also showed good enzyme inhibition of MTB ICL with IC(50) of 0.10 ± 0.01 µM. The docking studies also confirmed the binding potential of the compounds at the ICL active site.


Assuntos
Anilidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Isocitrato Liase/antagonistas & inibidores , Mycobacterium tuberculosis/enzimologia , Nitrocompostos/farmacologia , Anilidas/síntese química , Anilidas/química , Domínio Catalítico/efeitos dos fármacos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Isocitrato Liase/metabolismo , Modelos Moleculares , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Estereoisomerismo , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 20(15): 4313-6, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20615698

RESUMO

Various 5-nitro-2-furoic acid hydrazones were synthesized and evaluated for in vitro activities against log and starved phase culture of two mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among twenty one compounds, 5-nitro-N'-[(5-nitro-2-furyl)methylidene]-2-furohydrazide (4o) was found to be the most active compound in vitro with MICs of 2.65 and 10.64 microM against log- and starved-phase culture of MTB. Compound 4o also showed good enzyme inhibition of MTB ICL at 10 microM. The docking studies also confirmed the binding potential of the compounds at the ICL active site.


Assuntos
Antibacterianos/síntese química , Inibidores Enzimáticos/síntese química , Furanos/química , Furanos/síntese química , Hidrazinas/síntese química , Hidrazonas/química , Animais , Antibacterianos/química , Antibacterianos/toxicidade , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Chlorocebus aethiops , Simulação por Computador , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Furanos/toxicidade , Hidrazinas/química , Hidrazinas/toxicidade , Hidrazonas/síntese química , Hidrazonas/toxicidade , Isocitrato Liase/antagonistas & inibidores , Isocitrato Liase/metabolismo , Testes de Sensibilidade Microbiana , Mycobacterium/efeitos dos fármacos , Mycobacterium/enzimologia , Células Vero
5.
J Enzyme Inhib Med Chem ; 25(6): 765-72, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20569083

RESUMO

Fourteen 5-nitro-2,6-dioxohexahydro-4-pyrimidinecarboxamides (3a-n) were synthesized and evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multidrug-resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)), as well as their cytotoxicity and MTB isocitrate lyase (ICL) inhibition activity. 1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl)-4-[(5-nitro-2,6-dioxohexahydro-4-pyrimidinyl)carbonyl]piperazino-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3n) was found to be the most active compound in vitro with MICs of < 0.17 and 0.17 µM against log-phase MTB and MDR-TB, respectively. Some compounds showed 20-45% inhibition against MTB ICL at 10 µM.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Isocitrato Liase/antagonistas & inibidores , Mycobacterium/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antituberculosos/química , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Chlorocebus aethiops , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana Múltipla , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Isocitrato Liase/química , Isocitrato Liase/metabolismo , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium/crescimento & desenvolvimento , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Piperazinas , Ligação Proteica , Pirimidinas/química , Pirimidinas/metabolismo , Quinolinas , Tuberculose/tratamento farmacológico , Células Vero
6.
Chem Biol Drug Des ; 75(4): 381-91, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20148903

RESUMO

Twenty four novel 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetic acid amides were synthesized from phthalic anhydride and were subjected to in vitro and in vivo evaluation against log- and starved phase of mycobacterial species and Mycobacterium tuberculosis isocitrate lyase enzyme inhibition studies. Among the compounds screened, 2-(2-(4-bromo-2-fluorobenzyl)-1,2-dihydro-1-oxophthalazin-4-yl)-N-(2,6-dimethylphenyl)acetamide (5j) inhibited all eight mycobacterial species with MIC's ranging from 0.08 to 5.05 microm and was non-toxic to Vero cells till 126.43 microm. Four compounds were tested against starved culture of Mycobacterium tuberculosis and they inhibited with MIC's ranging from 3.78 to 23.2 microm. Some compounds showed 40-66% inhibition against Mycobacterium tuberculosis isocitrate lyase enzyme at 10 microm. The docking studies also confirmed the binding potential of the compounds at the isocitrate lyase active site. In the in vivo animal model, 5j reduced the mycobacterial load in lung and spleen tissues with 1.38 and 2.9-log10 protections, respectively, at 25 mg/kg body weight dose.


Assuntos
Acetamidas/química , Antituberculosos/síntese química , Ftalazinas/química , Acetamidas/síntese química , Acetamidas/farmacologia , Acetamidas/toxicidade , Antituberculosos/metabolismo , Antituberculosos/toxicidade , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Isocitrato Liase/química , Testes de Sensibilidade Microbiana , Ftalazinas/síntese química , Ftalazinas/farmacologia
7.
J Enzyme Inhib Med Chem ; 25(1): 105-10, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19929750

RESUMO

Nineteen 5-nitrothiazolylthiosemicarbazones were synthesized from 5-nitrothiazole by three-step synthesis and evaluated for in vitro activities against seven mycobacterial species. Among them, N-(5-nitro-1, 3-thiazol-2-yl)-2-((Z)-4-[(phenylmethyl)oxy]phenylmethylidene)hydrazine-1-carbothioamide (4m) was found to be the most active compound with a minimum inhibitory concentration (MIC) of 0.23 microM against Mycobacterium tuberculosis H37 Rv, and was three times more potent than isoniazid and equally active as rifampicin. Compound 4m also inhibited six non-tubercular mycobacteria with MICs ranging from 1.88 to 30.25 microM.


Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Mycobacterium/efeitos dos fármacos , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologia , Animais , Chlorocebus aethiops , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Especificidade da Espécie , Células Vero
8.
Eur J Med Chem ; 44(9): 3821-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19524332

RESUMO

An efficient synthesis of 1-methyl-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones was achieved by the reaction of 1-methyl-4-piperidone and aromatic aldehydes in the presence of pyrrolidine under solvent-free microwave irradiation. These dipolarophiles upon cycloaddition with nitrile oxide and azomethine ylides afford stereoselectively novel spiro-isoxazolines, pyrrolizines and pyrrolidines respectively in excellent yields. The spiro compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) using agar dilution method. Among the synthesized compounds, 1-methyl-4-(2,4-dichlorophenyl)pyrrolo(spiro[2.3'']oxindole)spiro[3.3']-1'-methylpiperidin-4'-one was found to be the most active with a minimum inhibitory concentration (MIC) of 1.76 and 0.88 microM against MTB and MDR-TB respectively.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Piperidonas/química , Piperidonas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Antibacterianos/síntese química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Piperidonas/síntese química , Pirrolidinas/síntese química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Tuberculose/tratamento farmacológico
9.
Nucleosides Nucleotides Nucleic Acids ; 28(2): 89-102, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19219739

RESUMO

Twelve novel zidovudine derivatives were prepared by modifying 5 '-hydroxyl group of sugar moiety (1-8) and 5-methyl group of thymidine nucleus (9-12) and characterized spectrally. The compounds were evaluated for anti-HIV-1, antitubercular and antibacterial activities. Compound (3-azido-tetrahydro-5- (3,4-dihydro-5-methyl-2,4-dioxopyrimidin-1(2H)-yl)furan-2-yl)methyl 7-(4-(2-phenylacetoyloxy)-3,5- dimethylpiperazin-1-yl)-5-(2-phenylacetoyloxyamino)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (5) was found to be the most potent anti-HIV-1 agent with EC(50) of 0.0012 microM against HIV-1(IIIB) and CC(50) of 34.05 microM against MT-4 with selectivity index of 28,375. Compound 5 inhibited Mycobacterium tuberculosis with MIC of 1.72 microM and inhibited four pathogenic bacteria with MIC of less than 1 microM.


Assuntos
Antibacterianos/síntese química , Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Zidovudina/análogos & derivados , Zidovudina/síntese química , Antibacterianos/farmacologia , Fármacos Anti-HIV/farmacologia , Bactérias/efeitos dos fármacos , Linhagem Celular , Desenho de Fármacos , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Zidovudina/farmacologia
10.
Arch Pharm (Weinheim) ; 342(2): 100-12, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19137533

RESUMO

Fifty one newer 1-(cyclopropyl/2,4-difluorophenyl/tert-butyl)-1,4-dihydro-8-methyl-6-nitro-4-oxo-7-(substituted secondary amino)quinoline-3-carboxylic acids were synthesized from 1,3-dichloro-2-methylbenzene and evaluated for in-vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)). Among the synthesized compounds, 1-cyclopropyl-1,4-dihydro-7-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)-8-methyl-6-nitro-4-oxoquinoline-3-carboxylic acid 9p was found to be the most active compound in vitro with a MIC value of 0.39 microM against MTB. Against MDR-TB, compound 7-(2-carboxy-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-1-cyclopropyl-1,4-dihydro-8-methyl-6-nitro-4-oxoquinoline-3-carboxylic acid 9n was found to be the most active with a MIC value of 0.09 microM.


Assuntos
Antituberculosos/síntese química , Butanos/química , Fluorbenzenos/química , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinas/síntese química , Quinolinas/síntese química , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium tuberculosis/crescimento & desenvolvimento , Pirazinas/química , Pirazinas/farmacologia , Pirazinas/toxicidade , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/toxicidade , Relação Estrutura-Atividade , Células Vero
11.
Bioorg Med Chem Lett ; 19(4): 1152-4, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19131245

RESUMO

Eighteen 5-nitrofuran-2-yl derivatives were prepared by reacting 5-nitro-2-furfural with various (sub)phenyl/pyridyl thiosemicarbazide using microwave irradiation. The compounds were tested for their in vitro activity against tubercular and various non-tubercular mycobacterium species in log-phase and 6-week-starved cultures. Compound N-(3,5-dibromopyridin-2-yl)-2-((5-nitrofuran-2-yl)methylene)hydrazinecarbothioamide (4r) was found to be the most potent compound (MIC: 0.22 microM) and was 3 times more active than standard isoniazid (INH) and equally active as rifampicin (RIF) in log-phase culture of Mycobacterium tuberculosis H37Rv. In starved M. tuberculosis H37Rv, 4r inhibited with MIC of 13.9 microM and was found to be 50 times more active than INH and slightly more active than RIF.


Assuntos
Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologia , Antituberculosos/farmacologia , Técnicas de Química Combinatória , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Nitrofuranos , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Tuberculose/microbiologia
12.
Biomed Pharmacother ; 63(1): 27-35, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18031974

RESUMO

Fifty-one novel 1-(cyclopropyl/2,4-difluorophenyl/t-butyl)-1,4-dihydro-6-fluoro-7-(sub secondary amino)-4-oxoquinoline-3-carboxylic acids were synthesized and evaluated for their antimycobacterial in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesized compounds, 7-(3-(diethylcarbamoyl)piperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (7l) was found to be the most active compound in vitro with MIC of 0.09 microM against MTB and MDR-TB respectively. In the in vivo animal model 7l decreased the mycobacterial load in lung and spleen tissues with 2.53- and 4.88-log10 protections respectively at a dose of 50mg/kg body weight.


Assuntos
Antituberculosos/farmacologia , Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , DNA Girase/metabolismo , Dermatite Fototóxica , Farmacorresistência Bacteriana Múltipla , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/enzimologia
13.
Biomed Pharmacother ; 63(1): 11-8, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18078735

RESUMO

Sixteen novel 3-nitro-2-(sub)-5,12-dihydro-5-oxobenzothiazolo[3,2-a]-1,8-naphthyridine-6-carboxylic acids were synthesized from 2,6-dimethoxynicotinic acid and 2-aminothiophenol and evaluated for their antitubercular activities in vitro and in vivo against Mycobacterium tuberculosis H(37) Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among the synthesized compounds, 2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-nitro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]-1,8-naphthyridine-6-carboxylic acid (10n) was found to be the most active compound in vitro with MIC of 0.19 and 0.04 microM against MTB and MTR-TB, respectively. Compound 10n showed promising activity against MDR-TB and was 208 and 1137 times more potent than gatifloxacin and isoniazid, respectively. In the in vivo animal model 10n decreased the mycobacterial load in lung and spleen tissues with 2.81 and 4.94-log(10) protections, respectively, at a dose of 50 mg/kg body weight.


Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Chlorocebus aethiops , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Células Vero
14.
Eur J Med Chem ; 44(1): 345-58, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18502542

RESUMO

Various 1-(substituted)-1,4-dihydro-6-nitro-4-oxo-7-(sub-secondary amino)-quinoline-3-carboxylic acids were synthesized from 2,4-dichlorobenzoic acid by six step synthesis. The compounds were evaluated for antimycobacterial in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the 48 synthesized compounds, 7-(4-((benzo[d][1,3]dioxol-5-yl)methyl)piperazin-1-yl)-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxoquinoline-3-carboxylic acid (8c) was found to be the most active compound in vitro with MIC of 0.08 and 0.16 microM against MTB and MDR-TB, respectively. In the in vivo animal model 8c decreased the bacterial load in lung and spleen tissues with 2.78 and 4.15-log10 protections, respectively, at the dose of 50 mg/kg body weight.


Assuntos
Antibacterianos/síntese química , Quinolinas/síntese química , Animais , Antibacterianos/farmacologia , Ácidos Carboxílicos , Chlorocebus aethiops , DNA Girase/efeitos dos fármacos , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/farmacologia , Esplenopatias/tratamento farmacológico , Esplenopatias/microbiologia , Relação Estrutura-Atividade , Células Vero
15.
Med Chem ; 4(5): 482-91, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18782045

RESUMO

Thirty four novel 7-fluoro/nitro-1,2-dihydro-5-oxo-8-(sub)-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids were synthesized from 2,4-dichlorobenzoic acid and 2,4-dichloro-5-fluoroacetophenone by multi step reaction, evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesized compounds, 8-[6-[[(1,1-dimethylethoxy)carbonyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-1,2-dihydro-7-nitro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid (10q) was found to be the most active compound in vitro with MIC of 0.08 microM and <0.08 microM against MTB and MDR-TB respectively. Compound 10q was found to be 4.5 and >570 times more potent than isoniazid against MTB and MDR-TB respectively. In the in vivo animal model 10q decreased the bacterial load in lung and spleen tissues with 2.51 and 3.71-log10 protections respectively at the dose of 50 mg/kg body weight.


Assuntos
Antituberculosos/farmacologia , Dermatite Fototóxica/patologia , Pulmão/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/farmacologia , Baço/efeitos dos fármacos , Tiazóis/farmacologia , Antituberculosos/síntese química , DNA Girase/metabolismo , Dermatite Fototóxica/metabolismo , Pulmão/microbiologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/crescimento & desenvolvimento , Quinolinas/síntese química , Baço/microbiologia , Relação Estrutura-Atividade , Tiazóis/síntese química
16.
J Med Chem ; 51(18): 5731-5, 2008 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-18714980

RESUMO

An atom economic and stereoselective synthesis of several spiro-piperidin-4-ones through 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin and alpha-amino acids viz . proline, phenylglycine, and sarcosine to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones is described. These compounds were evaluated for their in vitro and in vivo activity against Mycobacterium tuberculosis H37Rv (MTB), multidrug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)). Compound 4-(4-fluorophenyl)-5-phenylpyrrolo(spiro[2.3'']oxindole)spiro[3.3']-1'-methyl-5'-(4-fluorophenylmethylidene)piperidin-4'-one (4e) was found to be the most active in vitro with a MIC value of 0.07 microM against MTB and was 5.1 and 67.2 times more potent than isoniazid and ciprofloxacin, respectively. In vivo, compound 4e decreased the bacterial load in lung and spleen tissues with 1.30 and 3.73-log 10 protections respectively and was considered to be promising in reducing bacterial count in lung and spleen tissues.


Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Estereoisomerismo
17.
Bioorg Med Chem ; 16(6): 3408-18, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18304818

RESUMO

Various 2-(sub)-3-fluoro/nitro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid derivatives were synthesized from 2-aminothiophenol by a five-step reaction, evaluated for in-vitro and in-vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC2), and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the thirty-four synthesized compounds, 2-(3-(diethylcarbamoyl)piperidin-1-yl)-)-3-fluoro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid (7l) was found to be the most active compound in vitro with MIC of 0.18 and 0.08 microM against MTB and MTR-TB, respectively. Compound 7l was found to be 2 and 570 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in-vivo animal model 7l decreased the bacterial load in lung and spleen tissues with 2.78 and 3.12-log10 protections, respectively, at the dose of 50 mg/kg body weight.


Assuntos
Antituberculosos/química , Mycobacterium/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla , Pulmão/microbiologia , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/química , Baço/microbiologia , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 18(3): 1229-36, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18068979

RESUMO

Thirty novel 9-fluoro-2,3-dihydro-8,10-(mono/di-sub)-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acids were synthesized from 2,3,4,5-tetrafluoro benzoic acid and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from mycobacteria. Among the synthesized compounds, 10-[2-carboxy-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active compound in vitro with MIC99 of 0.19 microM and 0.09 microM against MTB and MTR-TB, respectively. In the in vivo animal model also the same compound decreased the bacterial load in lung and spleen tissues with 1.91 and 2.91--log10 protections, respectively, at the dose of 50mg/kg body weight. Compound 10-[(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active in the inhibition of the supercoiling activity of DNA gyrase with an IC(50) of 10.0 microg/mL. The results demonstrate the potential and importance of developing new oxazino quinolone derivatives against mycobacterial infections.


Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Fluoroquinolonas/química , Fluoroquinolonas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Inibidores da Topoisomerase II , Animais , Antituberculosos/química , Técnicas de Química Combinatória , DNA Girase/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fluoroquinolonas/síntese química , Gatifloxacina , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Camundongos , Estrutura Molecular , Ofloxacino/farmacologia , Baço/efeitos dos fármacos , Baço/microbiologia , Relação Estrutura-Atividade
19.
Bioorg Med Chem ; 16(5): 2558-69, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18078756

RESUMO

Thirty-four newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids were synthesized from 1,2,3,4-tetrafluoro benzene and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase. Among the synthesized compounds, 7-(1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinolin-2(1H)-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylic acid (13n) was found to be the most active compound in vitro with MIC of 0.16 and 0.33 microM against MTB and MDR-TB, respectively. In the in vivo animal model 13n decreased the bacterial load in lung and spleen tissues with 2.54 and 2.92-log10 protections, respectively, at the dose of 50mg/kg body weight. Compound 13n also inhibited the supercoiling activity of mycobacterial DNA gyrase with IC(50) of 30.0 microg/ml.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Ciclopropanos/química , Compostos de Flúor/síntese química , Compostos de Flúor/farmacologia , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/farmacologia , Aminação , Animais , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , DNA Girase/metabolismo , Compostos de Flúor/química , Hidroxiquinolinas/química , Estrutura Molecular , Mycobacterium/efeitos dos fármacos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/toxicidade , Relação Estrutura-Atividade , Inibidores da Topoisomerase II , Células Vero
20.
Bioorg Med Chem Lett ; 17(23): 6459-62, 2007 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17933535

RESUMO

An atom efficient, green protocol for the synthesis of fifteen 2-amino-6-methyl-4-aryl-8-[(E)-arylmethylidene]-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitriles in quantitative yields from the reaction of 1-methyl-3,5-bis[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones with malononitrile in presence of solid sodium ethoxide under solvent-free condition is described. The compounds were tested for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant tuberculosis (MDR-TB), and Mycobacterium smegmatis using agar dilution method. 2-Amino-4-[4-(dimethylamino)phenyl]-8-(E)-[4-(dimethylamino)phenyl]methylidene-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]-pyridine-3-carbonitrile was found to be the most potent compound (MIC: 0.43microM) against MTB and MDR-TB, being 100 times more active than standard, isoniazid against MDR-TB.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Catálise , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Testes de Sensibilidade Microbiana/métodos , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/fisiologia , Solventes
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