Design, synthesis and biological evaluation of ethyl 5‐(1‐benzyl‐1H‐indol‐5‐yl)isoxazole‐3‐carboxylates as antimycobacterial agents

Abstract : The continued prevalence of drug‐resistant Mycobacterium tuberculosis (Mtb) strains, particularly against first‐line antitubercular (anti‐TB) drugs, presents an impending public health threat that necessitates the exploration and development of New Chemical Entities (NCEs). In search of new anti‐TB leads, a library of ethyl 5‐(1‐benzyl‐1H‐indol‐5‐yl)isoxazole‐3‐carboxylates were generated through a strategy of scaffold hopping from the proven isoxazole‐3‐carboxylate‐based anti‐TB pharmacophore. We evaluated their antibacterial potential against a panel of pathogenic bacteria and MtbH37Rv strains. The majority of the compounds exhibited notable in vitro efficacy against the H37Rv strains (MIC 0.25 to 16 µg/mL) and were not cytotoxic with a Selectivity Index (SI) >10. Compound 5e (3,4‐dichlorobenzyl substituent) was found to be optimally active in the lot (MIC 0.25 µg/mL) and SI > 200. It also displayed equipotent activity against drug‐resistant Mtb (DR‐Mtb) strains. In addition, it demonstrated concentration‐dependent bactericidal activity in a time‐kill kinetic assay similar to first‐line anti‐TB drugs besides exhibiting synergistic activity with Streptomycin. Moreover, it complies with the drug‐likeness characteristic, making it a promising candidate for further exploration as a probable anti‐TB lead.