RESUMO
OBJECTIVES: The objective of this work was to synthesize 15 new 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(sub)phenyl/pyridylthiourea compounds and evaluate their in vitro and in vivo antimycobacterial activities. METHODS: 5-Cyclobutyloxazol-2-amine was reacted with 1,1'-thiocarbonyldiimidazole, followed by various substituted anilines and 2-amino pyridines to yield the 15 compounds, which were subjected to in vitro and in vivo evaluation against Mycobacterium tuberculosis H37Rv (MTB) and a clinical isolate of multidrug-resistant M. tuberculosis (MDR-TB). RESULTS: Among the 15 compounds screened, 7 compounds inhibited both MTB and MDR-TB in vitro with MICs of < 1 microM. In the in vivo screening, compound 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(2'-trifluoromethyl)phenylthiourea (compound 8) was equally active as isoniazid at the same dose level. CONCLUSIONS: Compound 8 was found to be the most active, with an in vitro MIC of 0.14 microM and was 2.5 and 80 times more active than isoniazid against MTB and MDR-TB, respectively. Compound 8 was non-toxic to Vero cells up to 183 microM, with a selectivity index of > 1307. In the in vivo animal model, compound 8 decreased the mycobacterium load in lung and spleen tissues with 2.8 and 3.94 log(10) reductions, respectively.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/síntese química , Piridinas/farmacologia , Tioureia/análogos & derivados , Tioureia/síntese química , Tioureia/farmacologia , Animais , Antituberculosos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Feminino , Isoniazida/farmacologia , Espectroscopia de Ressonância Magnética , Camundongos , Testes de Sensibilidade Microbiana , Piridinas/toxicidade , Relação Estrutura-Atividade , Sais de Tetrazólio , Tiazóis , Tioureia/toxicidade , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Células VeroRESUMO
Twenty 4-(5-cyclobutyloxazol-2-yl)thiosemicarbazones were synthesized and evaluated for preliminary in vitro and in vivo activity against Mycobacterium tuberculosis H37Rv (MTB) and multidrug-resistant Mycobacterium tuberculosis (MDR-TB). Among them, (4-bromophenyl)(phenyl)methanone N-(5-cyclobutyl-1,3-oxazol-2-yl)thiosemicarbazone 6q was found to be the most active compound in vitro with minimum inhibitory concentration of 0.05 microg/mL against MTB and MDR-TB. In the in vivo animal model 6q decreased the bacterial load in lung and spleen tissues with 2.1 log 10 and 3.72 log 10 protections, respectively, at 50 mg/kg body weight dose.
