2. Academic Validation
  3. Structure-based development of N-Arylindole derivatives as Pks13 inhibitors against Mycobacterium tuberculosis

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

  • Eur J Med Chem. 2025 Feb 5:283:117148. doi: 10.1016/j.ejmech.2024.117148.
Xuan Zhang 1,  Shichun Lun 2,  Yu-Xin Li 1,  Wei Zhang 1,  Ruo-Yi Zhou 1,  Ting Liu 1,  Fan Yang 1,  Jie Tang 3,  William R Bishai 4,  Li-Fang Yu 5
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China.
  • 2 Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD, 21231-1044, United States.
  • 3 Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China.
  • 4 Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD, 21231-1044, United States. Electronic address: wbishai1@jhmi.edu.
  • 5 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China. Electronic address: lfyu@sat.ecnu.edu.cn.
PMID: 39709795 DOI: 10.1016/j.ejmech.2024.117148
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.

Keywords

Antitubercular agents; N-Aryl indole; Pks13 inhibitor; Structure-guided optimization.

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