Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite

Autor:	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, Leticia Huertas Valentín
Rok vydání:	2020
Předmět:	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
Zdroj:	ACS Infectious Diseases. 6:1098-1109
ISSN:	2373-8227
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::be4ffbcdf78173cbc7773be3376915d1 https://doi.org/10.1021/acsinfecdis.9b00493 Zobrazit plný text záznamu