Benzo[d]thiazole-2-carbanilides as new anti-TB chemotypes: Design, synthesis, biological evaluation, and structure-activity relationship

Abstract

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.

Keywords: ATP phosphoribosyltransferase (HisG); Anti-TB (H(37)Rv) activity; Benzo[d]thiazole-2-carbanilides; CDI-Mediated amide coupling; Molecular docking; New anti-TB chemotypes.