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

  • Bioorg Med Chem Lett. 2024 Jan 15:98:129596. doi: 10.1016/j.bmcl.2023.129596.
Baiyuan Yang  1 ,  Paridhi Sukheja  2 ,  Bo Qin  2 ,  Gencheng Li  3 ,  Grant A L Bare  3 ,  Alessandro Cascioferro  2 ,  Melissa S Love  2 ,  H Michael Petrassi  2 ,  K Barry Sharpless  3 ,  Case W McNamara  2 ,  Arnab K Chatterjee  2
Affiliations
  • 1. Calibr, a Division of Scripps Research, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 2. Calibr, a Division of Scripps Research, La Jolla, CA 92037, USA.
  • 3. Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA.
PMID: 38142914 DOI: 10.1016/j.bmcl.2023.129596
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.
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