Antimycobacterial activities of novel 2-(sub)-3-fluoro/nitro-5, 12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid

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-oxobenzothiazoio[3,2a]quinoline-6-carboxylic acid (71) was found to be the most active compound in vitro with MIC of 0.18 and 0.08 mu M against MTB and MTR-TB, respectively. Compound 71 was found to be 2 and 570 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in-vivo animal model 71 decreased the bacterial load in lung and spleen tissues with 2.78 and 3.12 - log 10 protections, respectively, at the dose of 50 mg/kg body weight. (C) 2007 Elsevier Ltd. All rights reserved.