Intracellular and Extracellular Efficacy of Homoisoflavone Derivatives Against <i>Mycobacterium Tuberculosis</i>: Progress Toward Novel Antitubercular Agents

Tuberculosis (TB) remains a leading cause of death among infectious diseases globally, necessitating new drug discovery due to rising drug‐resistant strains. Homoisoflavones, a distinct subgroup of flavonoids characterized by their 3‐benzylidenechroman‐4‐one skeleton, are promising natural products for new antimicrobials. This study explored 42 homoisoflavone derivatives as potential anti‐TB agents. Several derivatives showed potent anti‐ Mycobacterium tuberculosis ( Mtb ) activity. Specifically, derivatives 19 , 22 , and 41 show good selectivity index and significantly inhibited the Mtb H37Rv strain (MIC 90 2.2, 3.8, and 1.9 μM, respectively). Derivatives 22 and 41 were particularly effective against the hypervirulent clinical isolate Mtb M299 (MIC 90 1.5 and 2.5 μM, respectively), surpassing the potency of rifampicin (MIC 90 3.3 μM). Furthermore, these derivatives inhibited intracellular Mtb H37Rv growth in infected macrophages, with derivative 41 proving most potent (IC 50 5.2 μM) due to its unique nitrofuranyl and piperidine groups. The study also established a structure‐activity relationship (SAR) for the homoisoflavone scaffold. In silico analyses suggest these compounds have good oral bioavailability and low toxicity. These findings highlight homoisoflavone derivatives as promising candidates for future anti‐TB drug development.