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

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.