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 language | English (US) |
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Article number | 117148 |
Journal | European Journal of Medicinal Chemistry |
Volume | 283 |
DOIs | |
State | Published - Feb 5 2025 |
Keywords
- Antitubercular agents
- N-Aryl indole
- Pks13 inhibitor
- Structure-guided optimization
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry