Phenylimidazole derivatives of 4-pyridone as dual inhibitors of bacterial enoyl-acyl carrier protein reductases FabI and FabK

Hideo Kitagawa; Tomohiro Ozawa; Sho Takahata; Maiko Iida; Jun Saito; Mototsugu Yamada

doi:10.1021/jm0705354

Phenylimidazole derivatives of 4-pyridone as dual inhibitors of bacterial enoyl-acyl carrier protein reductases FabI and FabK

J Med Chem. 2007 Sep 20;50(19):4710-20. doi: 10.1021/jm0705354. Epub 2007 Aug 22.

Authors

Hideo Kitagawa¹, Tomohiro Ozawa, Sho Takahata, Maiko Iida, Jun Saito, Mototsugu Yamada

Affiliation

¹ Medicinal Chemistry Research Laboratories, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. hideo_kitagawa@meiji.co.jp

PMID: 17713898
DOI: 10.1021/jm0705354

Abstract

FabI and FabK are bacterial enoyl-acyl carrier protein (ACP) reductases that catalyze the final and rate-limiting step of bacterial fatty acid biosynthesis (FAS) and are potential targets of novel antibacterial agents. We have reported 4-pyridone derivative 3 as a FabI inhibitor and phenylimidazole derivative 5 as a FabK inhibitor. Here, we will report phenylimidazole derivatives of 4-pyridone as FabI and FabK dual inhibitors based on an iterative medicinal chemistry and crystallographic study of FabK from Streptococcus pneumoniae/compound 26. A representative compound 6 showed strong FabI inhibitory (IC50 = 0.38 microM) and FabK inhibitory (IC50 = 0.0045 microM) activities with potent antibacterial activity against S. pneumoniae (MIC = 0.5 microg/mL). Since elevated MIC value was observed against S. pneumoniae mutant possessing one amino acid substitution in FabK, the antibacterial activity of the compound was considered to be due to the inhibition of FabK. Moreover, this compound showed no significant cytotoxicity (IC50 > 69 microM). These results support compound 6 as a novel agent for the treatment of bacterial infections.

MeSH terms

Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / genetics
Benzothiazoles / chemical synthesis*
Benzothiazoles / chemistry
Benzothiazoles / pharmacology
Binding Sites
Cell Line, Tumor
Crystallography, X-Ray
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / antagonists & inhibitors*
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / genetics
Escherichia coli Proteins / antagonists & inhibitors
Escherichia coli Proteins / genetics
Fatty Acid Synthase, Type II
Fatty Acids / antagonists & inhibitors
Fatty Acids / biosynthesis
Humans
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacology
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Mutation
Pyridones / chemical synthesis*
Pyridones / chemistry
Pyridones / pharmacology
Staphylococcus aureus / drug effects
Streptococcus pneumoniae / drug effects
Streptococcus pneumoniae / enzymology
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology
Urea / analogs & derivatives*
Urea / chemical synthesis
Urea / chemistry
Urea / pharmacology

Substances

1-((4-(4-(2-(3-(2,6-dichlorobenzyl)-2-methyl-4-oxopyridin-1(4H)-yl)ethyl)phenyl)-1H-imidazol-2-yl)methyl)-3-(6-(methylsulfonyl)benzo(d)thiazol-2-yl)urea
2-(4-(2-((3-(5-(Pyridin-2-ylthio)thiazol-2-yl)ureido)methyl)-1H-imidazol-4-yl)phenoxy)acetic acid
Anti-Bacterial Agents
Bacterial Proteins
Benzothiazoles
Escherichia coli Proteins
Fatty Acids
Imidazoles
Pyridones
Thiazoles
Urea
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
fabI protein, E coli
Fatty Acid Synthase, Type II