Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite
Fraser Cunningham, Jorge Esquivias, Raquel Fernández Menéndez, Arancha Pérez, A.C. Guardia, Jaime Escribano, Cristina Rivero, Mythily Vimal, Mónica Cacho, Paco de Dios-Antón, Maria Santos Martínez, Elena Jiménez, Leticia Huertas Valentín, María José Rebollo-López, Eva María López-Román, Verónica Sousa-Morcuende, Joaquín Rullás, Margaret Neu, Chun‐wa Chung, Robert H. Bates
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.