RESUMO
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).
Assuntos
Antibacterianos/farmacologia , Benzimidazóis/farmacologia , Carbono-Nitrogênio Ligases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Imidazóis/farmacologia , Ácidos Nicotínicos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Imidazóis/síntese química , Imidazóis/química , Ligantes , Testes de Sensibilidade Microbiana , Modelos Moleculares , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/química , Relação Estrutura-AtividadeRESUMO
Pyridine carboxamide-based inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified and optimized to a variety of topologically related scaffolds. In particular, the 2-methyl nicotinic acid scaffold was developed into inhibitors with improved biochemical (IC50-GT1b = 0.014 µM) and cell-based HCV replicon potency (EC50-GT1b = 0.7 µM). Biophysical and biochemical characterization identified this novel series of compounds as palm site binders to HCV polymerase.