Benzothiazole-2-carboxyarylalkylamides are reported as new class of potent anti-mycobacterial agents. Forty one target compounds have been synthesized following a green synthetic strategy using water as the reaction medium to construct the benzothiazole scaffold followed by (i) microwave-assisted catalyst-free, and (ii) ammonium chloride-catalysed solvent-free amide coupling. The antimycobacterial potency of the compounds was determined against H37Rv strain. Twelve compounds exhibited promising anti-TB activity in the range of 0.78-6.25 µg/mL and were found to be non-toxic (< 50% inhibition at 50 µg/mL) to HEK 293T cell lines with the therapeutic index (TI) of 8-64. The most promising anti-TB compound 5bf showed MIC 0.78 µg/mL (TI > 64). The molecular docking studies of 5bf predicts it to be a ligand for the M. tuberculosis HisG, the putative drug target for tuberculosis, and could serve as guiding principle for lead optimization.