Small Peptide Conjugates of Benzothiazole‐2‐Carboxylic Acids Targeting DprE1 Against Tuberculosis.

Inhibitors of Decaprenylphosphoryl‐β‐D‐ribose 2′‐epimerase (DprE1) are being thoroughly explored as potential pharmacological entities for the development of new anti‐tubercular therapeutics. In this context, benzothiazole‐bearing compounds have emerged as potential non‐covalent DprE1 inhibitors active against mycobacterium tuberculosis. In view of the promising anti‐tubercular activity of benzothiazole based non‐covalent DprE1 inhibitor TCA1; a series of thirty small peptide conjugates of benzothiazole‐2‐carboxylic acid has been synthesized and evaluated for their anti‐tubercular activity against the M.tb H37Ra strain by broth microdilution assay. Among the compounds tested, compounds methyl (6‐methoxybenzo[d]thiazole‐2 carbonyl)tryptophylalaninate and methyl (6‐methylbenzo[d]thiazole‐2‐carbonyl)tryptophylalaninate demonstrated potential anti‐tubercular activity with minimum inhibitory concentration (MIC) values of 4 and 8 μg/mL, respectively. These compounds were further identified to be mycobactericidal and are completely killing the microbes at 8‐16 μg/mL concentrations. Furthermore, the cytotoxicity study of most potent compound methyl (6‐methoxybenzo[d]thiazole‐2 carbonyl)tryptophylalaninate illustrated no significant toxicity to the human cell line HepG2. Moreover, synthesised compounds were subject to molecular docking, ADME studies and MM‐GBSA calculations. In silico studies suggest that these compounds show strong interactions with key amino acids in the binding pocket of DprE1 (PDBID: 4KW5) with the most active conjugates residing well (with docking scores of −08.49 and −7.902 kcal/mol). [ABSTRACT FROM AUTHOR]