Benzo[d]thiazole-2-carbanilides as new anti-TB chemotypes: Design, synthesis, biological evaluation, and structure-activity relationship.
Dhameliya TM, Tiwari R, Banerjee A, Pancholia S, Sriram D, Panda D, Chakraborti AK.
Tuberculosis is the second leading cause of deaths worldwide. The inadequacy of existing drugs to treat TB due to developed resistance and TB-HIV synergism urges for new anti-TB drugs. Seventy-two benzo[d]thiazole-2-carbanilides have been synthesized through CDI-mediated direct coupling of benzo[d]thiazole-2-carboxylic acids with aromatic amines using a three step methodology which includes a green protocol for synthesis of ethyl benzo[d]thiazole-2-carboxylates, precursor of the desired carboxylic acids. The compounds were evaluated in vitro for anti-tubercular activity against M. tuberculosis H37Rv (ATCC27294 strain). Thirty-two compounds exhibiting MIC values in the range of 0.78-6.25 μg/mL (1.9-23 μM) were subjected to cell viability test against RAW 264.7 cell lines and thirty compounds were found to be non-toxic (<50% inhibition). The most active compounds with MIC of 0.78 μg/mL (e.g., 4i, 4n, 4s, 4w, 6f, 6h, 6u, 7e, 7h, 7p, 7r and 7w) exhibit therapeutic index of 64. The structure activity relationship of the N-arylbenzo[d]thiazole-2-carboxamides has been established for anti-mycobacterial activity. Molecular docking suggests that the compounds 7w, 4i and 4n bind to the catalytic site of the enzyme ATP Phosphoribosyltransferase (HisG) and might be attributed to their anti-TB potential. These can serve as a new starting point for the development of anti-TB agents with therapeutic potential.