Design, synthesis, and structure–activity relationships of pyrazole derivatives as potential FabH inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (15), p.4657-4660
• Main Authors: Lv, Peng-Cheng, Sun, Juan, Luo, Yin, Yang, Ying, Zhu, Hai-Liang
• Format: Article
• Language: English
• Subjects: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - antagonists & inhibitors; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - metabolism; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Binding Sites; Biological and medical sciences; Computer Simulation; Design; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli; Escherichia coli Proteins - antagonists & inhibitors; Escherichia coli Proteins - metabolism; FabH inhibitors; Medical sciences; Pharmacology. Drug treatments; Pyrazole derivatives; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Structure-Activity Relationship; Synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.05.105

Fifty-six 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives were synthesized and developed as potent inhibitors of FabH. Escherichia coli FabH inhibitory assay was undertaken and the results suggested that compounds 12 and 13 were potent E. coli FabH inhibitors. Fatty acid biosynthesis is essential for bacterial survival. FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Fifty-six 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 1-(5-(4-fluorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (12) and 1-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (13) were potent inhibitors of E. coli FabH.