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

doi:10.1016/j.ejmech.2024.117148

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. Epub 2024 Dec 15.

Authors

Xuan Zhang¹, Shichun Lun², Yu-Xin Li¹, Wei Zhang¹, Ruo-Yi Zhou¹, Ting Liu¹, Fan Yang¹, Jie Tang³, William R Bishai⁴, Li-Fang Yu⁵

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.

MeSH terms

Antitubercular Agents* / chemical synthesis
Antitubercular Agents* / chemistry
Antitubercular Agents* / pharmacology
Bacterial Proteins / antagonists & inhibitors
Bacterial Proteins / metabolism
Dose-Response Relationship, Drug
Drug Development
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Indoles* / chemical synthesis
Indoles* / chemistry
Indoles* / pharmacology
Microbial Sensitivity Tests*
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Mycobacterium tuberculosis* / drug effects
Polyketide Synthases
Structure-Activity Relationship

Substances

Indoles
Antitubercular Agents
polyketide synthase Pks13, Mycobacterium tuberculosis
Enzyme Inhibitors
Bacterial Proteins
Polyketide Synthases