The urgent need for safer and innovative antitubercular agents remains a priority for the scientific community. In pursuit of this goal, we designed and evaluated novel 5-phenylfuran-2-carboxylic acid derivatives targeting Mycobacterium tuberculosis (Mtb) salicylate synthase (MbtI), a key enzyme, absent in humans, that plays a crucial role in Mtb virulence. Several potent MbtI inhibitors demonstrating significant antitubercular activity and a favorable safety profile were identified. Structure-guided optimization yielded 5-(3-cyano-5-isobutoxyphenyl)furan-2-carboxylic acid (1e), which exhibited strong MbtI inhibition (IC50 = 11.2 mu M) and a promising in vitro antitubercular activity (MIC99 = 32 mu M against M. bovis BCG). Esters of 1e were effectively loaded into poly(2-methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylamino)ethyl methacrylate) (PMPC-PDPA) polymersomes (POs) and delivered to intracellular mycobacteria, resulting in reduced Mtb viability. This study provides a foundation for the use of POs in the development of future MbtI-targeted therapies for tuberculosis.
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Cazzaniga, Giulia, Mori, Matteo, Griego, Anna, Scarpa, Edoardo, Moschetti, Giorgia, Muzzioli, Stefano, Stelitano, Giovanni, Chiarelli, Laurent R, Cocorullo, Mario, Casali, Emanuele, Porta, Alessio, Zanoni, Giuseppe, Tresoldi, Andrea, Pini, Elena, Batalha, Iris L, Battaglia, Giuseppe, Tuccinardi, Tiziano, Rizzello, Loris, Villa, Stefania, Meneghetti, Fiorella, (2025). Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy Journal Of Medicinal Chemistry 68, 5312-5332 