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Updated: Jun 4, 2025
System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
Published on: April 5, 2017
Structure-based development of N-Arylindole derivatives as Pks13 inhibitors against Mycobacterium tuberculosis
Xuan Zhang1, Shichun Lun2, Yu-Xin Li1
1Shanghai 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.
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.
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