RESUMEN
Ten new mefloquine-oxazolidine derivatives, 4-[(1S,8aR)-3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline (1: aryl=substituted phenyl) and 4-[(1S,8aR)-3-(heteroaryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline [2: heteroaryl=5-nitrothien-2-yl (2a); 5-nitrofuran-2-yl (2b) and 4H-imidazol-2-yl) (2c)], have been synthesized and evaluated against Mycobacterium tuberculosis. Compounds 1f (aryl=3-ethoxyphenyl), 1g (Ar=3,4,5-(MeO)(3)-C(6)H(2)) and 2c were slightly more active than mefloquine (MIC=33µM) with MICs=24.5, 22.5 and 27.4, respectively, whereas compounds 1e (aryl=3,4-(MeO)(2)-C(6)H(3)) and 2a (MICs=11.9 and 12.1µM, respectively) were ca. 2.7 times more active than mefloquine, with a better tuberculostatic activity than the first line tuberculostatic agent ethambutol (MIC=15.9). The compounds were also assayed against the MDR strain T113 and the same MICs were observed. Thus the new derivatives have advantages over such anti-TB drugs as isoniazid, rifampicin, ethambutol and ofloxacin, for which this strain is resistant. The most active compounds were not cytotoxic to Murine Macrophages Cells in a concentration near their MIC values.
Asunto(s)
Aldehídos/química , Antituberculosos/química , Antituberculosos/farmacología , Etambutol/farmacología , Mefloquina/química , Mycobacterium tuberculosis/efectos de los fármacos , Oxazoles/química , Animales , Antituberculosos/síntesis química , Células Cultivadas , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Etambutol/química , Mefloquina/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Mycobacterium tuberculosis/aislamiento & purificación , Oxazoles/farmacologíaRESUMEN
The present article describes a series of 21 Nâ'-benzylidene-2-oxo-2H-chromene-3-carbohydrazides 4a-4v, which were synthesized and evaluated for their cell viabilities in non-infected and Mycobacterium bovis Bacillus Calmette-Guerin-infected macrophages. Subsequently, the non-cytotoxic compounds 4c, 4g, 4h, 4j, 4l and 4t were assessed against Mycobacterium tuberculosis ATCC 27294 using the microplate Alamar Blue assay and the activity expressed as the minimum inhibitory concentration in µg/mL. These compounds exhibited a significant activity (50-100 µg/mL) when compared to the first-line drugs, such as pyrazinamide (PZA >100 µg/mL). These results could be considered a good starting point for further studies to develop new lead compounds to treat multidrug-resistant tuberculosis.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Cumarinas/química , Cumarinas/farmacología , Mycobacterium bovis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Animales , Bovinos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Hidrazonas/química , Hidrazonas/farmacología , Macrófagos/microbiología , Tuberculosis Bovina/tratamiento farmacológicoRESUMEN
Two series of N'-(E)-heteroaromatic-isonicotinohydrazide derivatives (3a-f and 4a-b) and 1-(7-chloroquinolin-4-yl)-2-[(heteroaromatic)methylene]hydrazone derivatives (5a-f and 6a-b) have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. Several compounds were noncytotoxic and exhibited significant minimum inhibitory concentration (MIC) activity (3.12, 2.50, 1.25, or 0.60 microg/mL), which can be compared to that of the first-line drugs ethambutol (3.12 microg/mL) and rifampicin (2.0 microg/ml). These results can be considered an important starting point for the rational design of new leads for anti-TB compounds.
Asunto(s)
Antituberculosos/síntesis química , Antituberculosos/farmacología , Hidrazonas/síntesis química , Hidrazonas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
A series of twenty-one 7-chloro-4-quinolinylhydrazones (3a-u) have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H(37)Rv. The compounds 3f, 3i and 3o were non-cytotoxic and exhibited an important minimum inhibitory concentration (MIC) activity (2.5 microg/mL), which can be compared with that of the first line drugs, ethambutol (3.12 microg/mL) and rifampicin (2.0 microg/mL). These results can be considered an important start point for the rational design of new leads for anti-TB compounds.
Asunto(s)
Antibacterianos/síntesis química , Antituberculosos/síntesis química , Antibacterianos/farmacología , Etambutol/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Relación Estructura-Actividad Cuantitativa , Rifampin/farmacología , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológicoRESUMEN
The present article describes a series of twenty-six N'-[(E)-(monosubstituted-benzylidene)]-2-pyrazinecarbohydrazide (4-29), which were synthesized and evaluated for their cell viabilities in non infected and infected macrophages with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). Afterwards, the non-cytotoxic compounds (4, 6, 8, 15, 21, 23, 24, 27 and 28) were assessed against Mycobacterium tuberculosis ATCC 27294 using the micro plate Alamar Blue assay (MABA) and the activity expressed as the minimum inhibitory concentration (MIC) in microg/mL. The compounds 6, 23, 27 and 28 exhibited a significant activity (50-100 microg/mL) when compared with first line drugs such as pyrazinamide and were not cytotoxic in their respective MIC values.