Discovery and optimization of antibacterial AccC inhibitors

Cliff C Cheng; Gerald W Shipps Jr; Zhiwei Yang; Binyuan Sun; Noriyuki Kawahata; Kyle A Soucy; Aileen Soriano; Peter Orth; Li Xiao; Paul Mann; Todd Black

doi:10.1016/j.bmcl.2009.10.057

Discovery and optimization of antibacterial AccC inhibitors

Bioorg Med Chem Lett. 2009 Dec 1;19(23):6507-14. doi: 10.1016/j.bmcl.2009.10.057. Epub 2009 Oct 28.

Authors

Cliff C Cheng¹, Gerald W Shipps Jr, Zhiwei Yang, Binyuan Sun, Noriyuki Kawahata, Kyle A Soucy, Aileen Soriano, Peter Orth, Li Xiao, Paul Mann, Todd Black

Affiliation

¹ Schering-Plough Research Institute, Cambridge, MA 02141, United States. [email protected]

PMID: 19875284
DOI: 10.1016/j.bmcl.2009.10.057

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).

MeSH terms

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

Substances

2-(2-chlorobenzylamino)-1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazo(4,5-b)pyridine-5-carboxamide
2-(2-chlorobenzylamino)-1-(cyclohexylmethyl)-1H-benzo(d)imidazole-5-carboxamide
Anti-Bacterial Agents
Benzimidazoles
Enzyme Inhibitors
Imidazoles
Ligands
Nicotinic Acids
Carbon-Nitrogen Ligases
biotin carboxylase