1. Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite
- Author
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Paco de Dios-Anton, Chun-wa Chung, Elena Jimenez, Maria Santos Martinez-Martinez, Fraser Cunningham, Mythily Vimal, Ana Guardia, Raquel Fernandez-Menendez, Arancha Pérez, Jaime Escribano, Jorge Esquivias, Robert H. Bates, María José Rebollo-López, Verónica Sousa-Morcuende, Monica Cacho, Joaquín Rullas, Eva Maria Lopez-Roman, Cristina Rivero, Margaret Neu, and Leticia Huertas Valentín
- Subjects
0301 basic medicine ,Stereochemistry ,Metabolite ,030106 microbiology ,Mycobacterium tuberculosis ,03 medical and health sciences ,chemistry.chemical_compound ,Bacterial Proteins ,3-Oxoacyl-(Acyl-Carrier-Protein) Synthase ,Moiety ,Binding site ,chemistry.chemical_classification ,Indazole ,Aniline Compounds ,Binding Sites ,ATP synthase ,biology ,biology.organism_classification ,Anti-Bacterial Agents ,Sulfonamide ,030104 developmental biology ,Infectious Diseases ,chemistry ,biology.protein ,DNA Damage - Abstract
In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.
- Published
- 2020
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