Phenylimidazole derivatives of 4-pyridone as dual inhibitors of bacterial enoyl-acyl carrier protein reductases FabI and FabK.
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.
Kitagawa
Hideo
H
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
Ozawa
Tomohiro
T
Takahata
Sho
S
Iida
Maiko
M
Saito
Jun
J
Yamada
Mototsugu
M
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000235:genetics; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D054889:Fatty Acid Synthase, Type II; D005227:Fatty Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C523630:1-((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; C528514:2-(4-(2-((3-(5-(Pyridin-2-ylthio)thiazol-2-yl)ureido)methyl)-1H-imidazol-4-yl)phenoxy)acetic acid; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D052160:Benzothiazoles; D029968:Escherichia coli Proteins; D005227:Fatty Acids; D007093:Imidazoles; D011728:Pyridones; D013844:Thiazoles; D014508:Urea; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); C493924:fabI protein, E coli; D054889:Fatty Acid Synthase, Type II