ABSTRACT Telacebec ( Q203 ) and lansoprazole sulfide (LPZS) are promising lead molecules in the development of new antitubercular agents. In this study, a series of 15 thiazole‐acetamide derivatives ( 5a‐ ‐ 5o ) were rationally designed and synthesized through bioisosteric modification of the key pharmacophores of Q203 and LPZS. Among the synthesized derivatives, Compounds 5c and 5d exhibited the moderate activity against Mycobacterium tuberculosis ( M. tuberculosis /Mtb) H37Ra, with minimum inhibitory concentration 99 (MIC 99 ) values of 16 and 32 µg/mL, respectively. These compounds also demonstrated half‐maximal inhibitory concentration (IC 50 ) values of 1.84 ± 1.05 µM ( 5c ) and 0.73 ± 0.13 µM ( 5d ), comparable to the reference drug isoniazid (INH). Cytotoxicity studies in mouse fibroblast cells revealed Compounds 5c and 5d with high selectivity index values, indicating selective inhibition of M. tuberculosis with low cytotoxicity. Molecular docking and dynamics studies of 5c with the QcrB subunit of Mtb cytochrome bcc‐aa 3 supercomplex (PDB ID: 7E1W) revealed key interactions with the conserved residues Thr313 and Ala179, providing mechanistic insight into its antitubercular activity. Although Compounds 5c and 5d did not yet achieve MIC 99 values comparable to reference drugs, they represent a promising scaffold for further optimization and development as antitubercular agents.
Kumar et al. (Mon,) studied this question.