Design, synthesis, and biological evaluation of coumarin derivatives against tuberculosis: a pharmacophore-based approach.

Abstract

Rising cases of drug resistance tuberculosis including multidrug-resistant and extensively drug-resistant emphasize the need for development of drugs with novel mechanism of action. The study aimed to explore novel inhibitors targeting Mycobacterium thymidine monophosphate kinase (Mtb TMPK), a promising but unexplored drug target for tuberculosis treatment. A library of 200 coumarin derivatives was rationally designed and screened against Mtb TMPK, an essential enzyme in nucleotide biosynthesis of mycobacterium tuberculosis. Common feature pharmacophore modeling was performed to identify crucial structural features required for Mtb TMPK inhibition. Molecular docking and ADMET analysis were conducted to prioritize 14 coumarin-piperazine-acetamide derivatives for synthesis. In order to assess the in vitro antitubercular potential of synthesized compounds, the REMA assay was performed. Compound S135, S144, and S146 have shown MIC of 0.06 µg/mL, comparable to the MIC of isoniazid 0.05 µg/mL. All synthesized compounds exhibited promising activity with MIC not exceeding 1 µg/mL, demonstrated the antitubercular potential of designed coumarin analogs. As the design strategy aimed to surpass the issue of whole-cell activity associated with previous Mtb TMPK inhibitors, these results could serve as foundation for this field, supported with green signal from in vitro cytotoxicity study. The findings truly emphasize on Mtb TMPK inhibition assays to fix the mode of action, which could ultimately pave the way for preclinical studies on these derivatives as future perspective.