PMID:19875284
| Citation |
Cheng, CC, Shipps, GW Jr, Yang, Z, Sun, B, Kawahata, N, Soucy, KA, Soriano, A, Orth, P, Xiao, L, Mann, P and Black, T (2009) Discovery and optimization of antibacterial AccC inhibitors. Bioorg. Med. Chem. Lett. 19:6507-14 |
|---|---|
| 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). |
| Links |
PubMed Online version:10.1016/j.bmcl.2009.10.057 |
| Keywords |
Anti-Bacterial Agents/chemical synthesis; Anti-Bacterial Agents/chemistry; Anti-Bacterial Agents/pharmacology; Benzimidazoles/chemical synthesis; Benzimidazoles/chemistry; Benzimidazoles/pharmacology; Carbon-Nitrogen Ligases/antagonists & inhibitors; Crystallography, X-Ray; Drug Discovery; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/pharmacology; Escherichia coli/drug effects; Imidazoles/chemical synthesis; Imidazoles/chemistry; Imidazoles/pharmacology; Ligands; Microbial Sensitivity Tests; Models, Molecular; Nicotinic Acids/chemical synthesis; Nicotinic Acids/chemistry; Nicotinic Acids/pharmacology; Structure-Activity Relationship |
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