Synthesis and structure-activity relationships of aryl fluorosulfate-based inhibitors as novel antitubercular agents

Abstract

To identify new compounds that can effectively inhibit Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), we screened, synthesized, and evaluated a series of novel aryl fluorosulfate derivatives for their in vitro inhibitory activity against Mtb. Compound 21b exhibited an in vitro minimum inhibitory concentration (MIC) of 0.06 µM against Mtb, no cytotoxicity against both HEK293T and HepG2 mammalian cell lines, and had good in vivo mouse plasma exposure and lung concentration with a 20 mg/kg oral dose, which supports advanced development as a new chemical entity for TB treatment.

Keywords: Anti-TB activity; Aryl fluorosulfate; Mycobacterium tuberculosis; Pharmacokinetic; Structure–activity relationship studies; SuFEx; Sulfur (VI) fluoride exchange.