RESUMO
Efflux inhibition is proven bacterial machinery responsible for removal of bacterial wastage including antibiotics. Recently, efflux inhibitors (EI) have been tested with encouraging results as an adjuvant therapy for treatment of tuberculosis (TB). Although, EI have emerged as innovative approach of treatment for multi drug resistant (MDR) & extensively drug resistant tuberculosis (XDR-TB), toxicity profile limits their wider use. To address this issue, we have attempted synthesizing hybrid molecules those results by combining known EI and triazole. This synthesis was aimed to arrive at structure that possesses pharmacophore from known EI. Synthesized molecules were evaluated as growth inhibitors (GI) and Efflux inhibitor of TB initially against Mycobacterium smegmatis mc(2)155. Pharmacologically active compounds were then tested for their cytotoxicity to further narrow down search. Most active compounds 144, 145, 154 and 163 were then tested for their GEI action against Mycobacterium tuberculosis (Mtb). Synthesized compounds were also tested for their synergistic action with first line and second line anti-TB drugs and ethidium bromide (EtBr). We arrived at compound 135 as most potent dual inhibitor of tuberculosis.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Triazóis/química , Antituberculosos/síntese química , Células Cultivadas , Técnicas de Química Sintética , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Humanos , Macrófagos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimentoRESUMO
In continuation of our research program for new antituberculosis drugs, we have designed, synthesized and evaluated antimycobacterial activity of new series of 1-[3-(4-benzotriazol-1/2-yl-3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-3-substituted-thiourea derivatives against different Mycobacterium species i.e. M. tuberculosis, M. avium and M. intracellulare in an agar dilution method. Compound 17 exhibited excellent antimycobacterial activity (in vitro) against drug sensitive and resistant clinical isolates of M. tuberculosis. Its MIC value is equivalent to linezolid and superior to isoniazid against all these strains.
Assuntos
Antituberculosos/síntese química , Oxazolidinonas/síntese química , Tioureia/análogos & derivados , Tioureia/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium/classificação , Mycobacterium/efeitos dos fármacos , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Tioureia/farmacologiaRESUMO
A series of novel (un)substituted benzotriazolyl oxazolidinone derivatives has been synthesized and tested for in vitro antibacterial activities by MIC determination against a panel of susceptible and resistant Gram-positive and Gram-negative microorganisms, some of which are resistant to methicillin and vancomycin. Compounds 20, 21, 24, 29 and 30 from this series were found to be equipotent or more potent than linezolid in vitro.
