title: Discovery and optimization of antibacterial AccC inhibitors.
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-benzo[d]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-imidazo[4,5-b]pyridine-5-carboxamide (40). This compound is a potent and selective inhibitor of bacterial AccC with an IC(50) of 20 nM and a MIC of 0.8 microg/mL against a sensitized strain of Escherichia coli (HS294 E. coli).
authors.affiliation: Schering-Plough Research Institute, Cambridge, MA 02141, United States. cccheng@alum.mit.edu
authors.forename: Cliff C
authors.initials: CC
authors.lastname: Cheng
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Shipps
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yang
authors.forename: Binyuan
authors.initials: B
authors.lastname: Sun
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kawahata
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Soucy
authors.forename: Aileen
authors.initials: A
authors.lastname: Soriano
authors.forename: Peter
authors.initials: P
authors.lastname: Orth
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.forename: Paul
authors.initials: P
authors.lastname: Mann
authors.forename: Todd
authors.initials: T
authors.lastname: Black
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009539:Nicotinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C546446:2-(2-chlorobenzylamino)-1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazo(4,5-b)pyridine-5-carboxamide; C546447:2-(2-chlorobenzylamino)-1-(cyclohexylmethyl)-1H-benzo(d)imidazole-5-carboxamide; D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008024:Ligands; D009539:Nicotinic Acids; D019731:Carbon-Nitrogen Ligases; C019791:biotin carboxylase