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Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-03-20 , DOI: 10.1021/acsinfecdis.9b00493 Fraser Cunningham 1 , Jorge Esquivias 1 , Raquel Fernández-Menéndez 1 , Arancha Pérez 1 , Ana Guardia 1 , Jaime Escribano 1 , Cristina Rivero 1 , Mythily Vimal 2 , Mónica Cacho 1 , Paco de Dios-Antón 1 , María Santos Martínez-Martínez 1 , Elena Jiménez 1 , Leticia Huertas Valentín 1 , María José Rebollo-López 1 , Eva María López-Román 1 , Verónica Sousa-Morcuende 1 , Joaquín Rullas 1 , Margaret Neu 2 , Chun-Wa Chung 2 , Robert H Bates 1
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-03-20 , DOI: 10.1021/acsinfecdis.9b00493 Fraser Cunningham 1 , Jorge Esquivias 1 , Raquel Fernández-Menéndez 1 , Arancha Pérez 1 , Ana Guardia 1 , Jaime Escribano 1 , Cristina Rivero 1 , Mythily Vimal 2 , Mónica Cacho 1 , Paco de Dios-Antón 1 , María Santos Martínez-Martínez 1 , Elena Jiménez 1 , Leticia Huertas Valentín 1 , María José Rebollo-López 1 , Eva María López-Román 1 , Verónica Sousa-Morcuende 1 , Joaquín Rullas 1 , Margaret Neu 2 , Chun-Wa Chung 2 , Robert H Bates 1
Affiliation
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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.
中文翻译：
探索β-酮酰基-ACP合酶抑制剂GSK3011724A的SAR和围绕遗传毒性代谢物的优化。
在优化抑制结核分枝杆菌的β-酮酰基-ACP合酶（KasA）的新型吲唑磺酰胺系列的过程中，鉴定了诱变的苯胺代谢产物。因此，进一步的铅优化工作致力于通过去除嵌入的苯胺部分或改变其空间或电子环境来消除这一关键责任。尽管相对于目标的狭窄SAR空间最终使该目标无法实现，但仍围绕该未充分开发的结核病目标的结合位点产生了关键的结构知识，以为未来的发现工作提供信息。
更新日期：2020-03-20
中文翻译：
探索β-酮酰基-ACP合酶抑制剂GSK3011724A的SAR和围绕遗传毒性代谢物的优化。
在优化抑制结核分枝杆菌的β-酮酰基-ACP合酶（KasA）的新型吲唑磺酰胺系列的过程中，鉴定了诱变的苯胺代谢产物。因此，进一步的铅优化工作致力于通过去除嵌入的苯胺部分或改变其空间或电子环境来消除这一关键责任。尽管相对于目标的狭窄SAR空间最终使该目标无法实现，但仍围绕该未充分开发的结核病目标的结合位点产生了关键的结构知识，以为未来的发现工作提供信息。
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