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
  • 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: [email protected].
  • 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: [email protected].
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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