Discovery and optimization of antibacterial AccC inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 23; pp. 6507 - 6514
• Main Authors: Cheng, Cliff C., Shipps, Gerald W., Yang, Zhiwei, Sun, Binyuan, Kawahata, Noriyuki, Soucy, Kyle A., Soriano, Aileen, Orth, Peter, Xiao, Li, Mann, Paul, Black, Todd
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.12.2009; Elsevier
• Subjects: ACCase; AccC; Acetyl coenzyme-A carboxylase; AFFINITY; ALIS: Automated Ligand Identification System; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; AS-MS: Affinity-Selection Mass Spectrometry; BASIC BIOLOGICAL SCIENCES; BCCP; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; BIOTIN; Biotin carboxyl carrier protein; Biotin carboxylase; Carbon-Nitrogen Ligases - antagonists & inhibitors; CARBOXYLASE; Crystallography, X-Ray; DESIGN; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; ESCHERICHIA COLI; Escherichia coli - drug effects; GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; HS294 E. coli; IDENTIFICATION SYSTEMS; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Ligands; Medical sciences; MIC; Microbial Sensitivity Tests; Models, Molecular; Nicotinic Acids - chemical synthesis; Nicotinic Acids - chemistry; Nicotinic Acids - pharmacology; OPTIMIZATION; PATHOGENS; Pharmacology. Drug treatments; STRAINS; Structure Based Drug Design (SBDD); Structure-Activity Relationship; Acetyl coenzyme-A carboxylase; ALIS: Automated Ligand Identification System; HS294 E. coli; BCCP; Biotin carboxyl carrier protein; MIC; AS-MS: Affinity-Selection Mass Spectrometry; Structure Based Drug Design (SBDD); Biotin carboxylase; ACCase; AccC; Molecular structure; Ligand; Escherichia coli; ALIS: Automated Ligand Identification; Optimization; System; Spectrometry; Imidazopyridine derivatives; Acetyl-CoA carboxylase; Structure activity relation; Ligases; Bacteria; Chemical synthesis; Carrier protein; Enterobacteriaceae; Carbon-carbon ligases; Automation; Carbon-nitrogen ligases; Enzyme; AS-MS: Affinity-Selection Mass; X ray diffraction; In vitro; Benzimidazole derivatives; Affinity; Inhibitor; Antibacterial agent; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.10.057

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)-1 H-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-1 H-inden-1-yl)-1 H-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 μg/mL against a sensitized strain of Escherichia coli (HS294 E. coli).