RESUMEN

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.

Asunto(s)

Analgésicos/farmacología , Antibacterianos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antiulcerosos/farmacología , Microondas , Pirazolonas/farmacología , Ácido Acético , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Antiulcerosos/administración & dosificación , Antiulcerosos/química , Bacterias/efectos de los fármacos , Carragenina/administración & dosificación , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Pirazolonas/administración & dosificación , Pirazolonas/química , Ratas , Relación Estructura-Actividad

RESUMEN

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.

Asunto(s)

Antituberculosos/síntesis química , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/farmacología , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

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.

Asunto(s)

Anilidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Isocitratoliasa/antagonistas & inhibidores , Mycobacterium tuberculosis/enzimología , Nitrocompuestos/farmacología , Anilidas/síntesis química , Anilidas/química , Dominio Catalítico/efectos de los fármacos , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Isocitratoliasa/metabolismo , Modelos Moleculares , Estructura Molecular , Nitrocompuestos/síntesis química , Nitrocompuestos/química , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

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.

Asunto(s)

Antibacterianos/síntesis química , Inhibidores Enzimáticos/síntesis química , Furanos/química , Furanos/síntesis química , Hidrazinas/síntesis química , Hidrazonas/química , Animales , Antibacterianos/química , Antibacterianos/toxicidad , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Dominio Catalítico , Chlorocebus aethiops , Simulación por Computador , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/toxicidad , Furanos/toxicidad , Hidrazinas/química , Hidrazinas/toxicidad , Hidrazonas/síntesis química , Hidrazonas/toxicidad , Isocitratoliasa/antagonistas & inhibidores , Isocitratoliasa/metabolismo , Pruebas de Sensibilidad Microbiana , Mycobacterium/efectos de los fármacos , Mycobacterium/enzimología , Células Vero

RESUMEN

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.

Asunto(s)

Antibacterianos/síntesis química , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Isocitratoliasa/antagonistas & inhibidores , Mycobacterium/efectos de los fármacos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antituberculosos/química , Antituberculosos/metabolismo , Antituberculosos/farmacología , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Chlorocebus aethiops , Simulación por Computador , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Isocitratoliasa/química , Isocitratoliasa/metabolismo , Ligandos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium/crecimiento & desarrollo , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/crecimiento & desarrollo , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Piperazinas , Unión Proteica , Pirimidinas/química , Pirimidinas/metabolismo , Quinolinas , Tuberculosis/tratamiento farmacológico , Células Vero

RESUMEN

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.

Asunto(s)

Acetamidas/química , Antituberculosos/síntesis química , Ftalazinas/química , Acetamidas/síntesis química , Acetamidas/farmacología , Acetamidas/toxicidad , Antituberculosos/metabolismo , Antituberculosos/toxicidad , Sitios de Unión , Dominio Catalítico , Simulación por Computador , Isocitratoliasa/química , Pruebas de Sensibilidad Microbiana , Ftalazinas/síntesis química , Ftalazinas/farmacología

RESUMEN

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.

Asunto(s)

Antituberculosos/síntesis química , Antituberculosos/farmacología , Mycobacterium/efectos de los fármacos , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/farmacología , Animales , Chlorocebus aethiops , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Especificidad de la Especie , Células Vero

RESUMEN

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.

Asunto(s)

Antibacterianos/química , Antibacterianos/farmacología , Piperidonas/química , Piperidonas/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Antibacterianos/síntesis química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Piperidonas/síntesis química , Pirrolidinas/síntesis química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Tuberculosis/tratamiento farmacológico

RESUMEN

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.

Asunto(s)

Antibacterianos/síntesis química , Fármacos Anti-VIH/síntesis química , VIH-1/efectos de los fármacos , Zidovudina/análogos & derivados , Zidovudina/síntesis química , Antibacterianos/farmacología , Fármacos Anti-VIH/farmacología , Bacterias/efectos de los fármacos , Línea Celular , Diseño de Fármacos , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Relación Estructura-Actividad , Zidovudina/farmacología

RESUMEN

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.

Asunto(s)

Antituberculosos/síntesis química , Butanos/química , Fluorobencenos/química , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Pirazinas/síntesis química , Quinolinas/síntesis química , Animales , Antituberculosos/química , Antituberculosos/farmacología , Antituberculosos/toxicidad , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium smegmatis/crecimiento & desarrollo , Mycobacterium tuberculosis/crecimiento & desarrollo , Pirazinas/química , Pirazinas/farmacología , Pirazinas/toxicidad , Quinolinas/química , Quinolinas/farmacología , Quinolinas/toxicidad , Relación Estructura-Actividad , Células Vero

RESUMEN

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.

Asunto(s)

Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/farmacología , Antituberculosos/farmacología , Técnicas Químicas Combinatorias , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Nitrofuranos , Relación Estructura-Actividad , Tiosemicarbazonas/química , Tuberculosis/microbiología

RESUMEN

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.

Asunto(s)

Antibacterianos/síntesis química , Quinolinas/síntesis química , Animales , Antibacterianos/farmacología , Ácidos Carboxílicos , Chlorocebus aethiops , Girasa de ADN/efectos de los fármacos , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/microbiología , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Quinolinas/farmacología , Enfermedades del Bazo/tratamiento farmacológico , Enfermedades del Bazo/microbiología , Relación Estructura-Actividad , Células Vero

RESUMEN

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.

Asunto(s)

Antituberculosos/farmacología , Fluoroquinolonas/síntesis química , Fluoroquinolonas/farmacología , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Animales , Girasa de ADN/metabolismo , Dermatitis Fototóxica , Farmacorresistencia Bacteriana Múltiple , Femenino , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium smegmatis/enzimología

RESUMEN

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.

Asunto(s)

Antituberculosos/síntesis química , Antituberculosos/farmacología , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Animales , Chlorocebus aethiops , Femenino , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Células Vero

RESUMEN

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.

Asunto(s)

Antituberculosos/farmacología , Dermatitis Fototóxica/patología , Pulmón/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Quinolinas/farmacología , Bazo/efectos de los fármacos , Tiazoles/farmacología , Antituberculosos/síntesis química , Girasa de ADN/metabolismo , Dermatitis Fototóxica/metabolismo , Pulmón/microbiología , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/crecimiento & desarrollo , Quinolinas/síntesis química , Bazo/microbiología , Relación Estructura-Actividad , Tiazoles/síntesis química

RESUMEN

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.

Asunto(s)

Antituberculosos/síntesis química , Antituberculosos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Estereoisomerismo

RESUMEN

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.

Asunto(s)

Antituberculosos/química , Mycobacterium/efectos de los fármacos , Quinolinas/farmacología , Animales , Antituberculosos/farmacología , Farmacorresistencia Bacteriana Múltiple , Pulmón/microbiología , Pruebas de Sensibilidad Microbiana , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Quinolinas/química , Bazo/microbiología , Relación Estructura-Actividad

RESUMEN

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.

Asunto(s)

Antibacterianos/síntesis química , Antibacterianos/farmacología , Ciclopropanos/química , Compuestos de Flúor/síntesis química , Compuestos de Flúor/farmacología , Hidroxiquinolinas/síntesis química , Hidroxiquinolinas/farmacología , Aminación , Animales , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Girasa de ADN/metabolismo , Compuestos de Flúor/química , Hidroxiquinolinas/química , Estructura Molecular , Mycobacterium/efectos de los fármacos , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/toxicidad , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II , Células Vero

RESUMEN

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.

Asunto(s)

Antituberculosos/síntesis química , Antituberculosos/farmacología , Fluoroquinolonas/química , Fluoroquinolonas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Inhibidores de Topoisomerasa II , Animales , Antituberculosos/química , Técnicas Químicas Combinatorias , Girasa de ADN/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Fluoroquinolonas/síntesis química , Gatifloxacina , Pulmón/efectos de los fármacos , Pulmón/microbiología , Ratones , Estructura Molecular , Ofloxacino/farmacología , Bazo/efectos de los fármacos , Bazo/microbiología , Relación Estructura-Actividad

RESUMEN

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.

Asunto(s)

Antibacterianos/síntesis química , Antibacterianos/farmacología , Nitrilos/síntesis química , Nitrilos/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Catálisis , Evaluación Preclínica de Medicamentos/métodos , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/fisiología , Solventes