Structure-based development of N-Arylindole derivatives as Pks13 inhibitors against Mycobacterium tuberculosis

Xuan Zhang, Shichun Lun, Yu Xin Li, Wei Zhang, Ruo Yi Zhou, Ting Liu, Fan Yang, Jie Tang, William R. Bishai, Li Fang Yu

Research output: Contribution to journalArticlepeer-review

Abstract

Targeting the biosynthetic pathway of mycolic acid is highly attractive to researchers in the field of novel anti-tubercular drug development. Pks13-TE is an essential catalytic component in the last assembling step of mycolic acid, and the co-crystal structures of the Pks13-TE-inhibitor complex provide insight into ligand recognition. Based on a structure-guided strategy, N-aryl indole derivatives were designed, synthesized, and evaluated for their antitubercular activities. Compound 44 was identified as the most promising compound with high potency against M. tb H37Rv (MIC = 0.07 μM) and a favorable metabolic profile in human liver microsomes. Moreover, compound 44 exhibited oral bioavailability in a serum inhibition titration (SIT) assay, which warrants further development.

Original languageEnglish (US)
Article number117148
JournalEuropean Journal of Medicinal Chemistry
Volume283
DOIs
StatePublished - Feb 5 2025

Keywords

  • Antitubercular agents
  • N-Aryl indole
  • Pks13 inhibitor
  • Structure-guided optimization

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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