Discovery and optimization of antibacterial AccC inhibitors |
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Authors: | Cliff C Cheng Gerald W Shipps Zhiwei Yang Binyuan Sun Noriyuki Kawahata Kyle A Soucy Aileen Soriano Peter Orth Li Xiao Paul Mann Todd Black |
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Institution: | 1. Schering-Plough Research Institute, 320 Bent Street, Cambridge, MA 02141, United States;2. Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States |
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Abstract: | The biotin carboxylase (AccC) is part of the multi-component bacterial acetyl coenzyme-A carboxylase (ACCase) and is essential for pathogen survival. We describe herein the affinity optimization of an initial hit to give 2-(2-chlorobenzylamino)-1-(cyclohexylmethyl)-1H-benzod]imidazole-5-carboxamide (1), which was identified using our proprietary Automated Ligand Identification System (ALIS).1 The X-ray co-crystal structure of 1 was solved and revealed several key interactions and opportunities for further optimization in the ATP site of AccC. Structure Based Drug Design (SBDD) and parallel synthetic approaches resulted in a novel series of AccC inhibitors, exemplified by (R)-2-(2-chlorobenzylamino)-1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazo4,5-b]pyridine-5-carboxamide (40). This compound is a potent and selective inhibitor of bacterial AccC with an IC50 of 20 nM and a MIC of 0.8 μg/mL against a sensitized strain of Escherichia coli (HS294 E. coli). |
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