Antimycobacterial and phototoxic evaluation of novel 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto [3,2-a]quinoline-3-carboxylic acid

Several newer 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3] thiazeto[3,2-a] quinoline-3-carboxylic acids (10-11a-q) were synthesised from 3,4-difluoro aniline and 3-fluoro-4-nitro aniline by nine-step synthesis. The compounds were evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multidrug-resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) as well as being tested for their ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesised compounds, 7-(1,4-dioxa-8-azaspiro[4.5] dec-8-yl)-6-nitro-4-oxo-4H-[1,3] thiazeto[3,2-a] quinoline-3-carboxylic acid (111) was found to be the most active compound in vitro, with minimum inhibitory concentrations (MICs) of 0.09 mu M and < 0.09 mu M against MTB and MTR-TB, respectively. Compound 111 was found to be 4 times and >506 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in vivo animal model, 111 decreased the bacterial load in lung and spleen tissues by 30% and 42%, respectively, at a dose of 50 mg/kg body weight. (C) 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.