title: Design, synthesis and antibacterial activities of vanillic acylhydrazone derivatives as potential β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors.
abstract: 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 Gram-negative bacteria. A series of acylhydrazone derivatives were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong broad-spectrum antibacterial activity. Compounds with potent antibacterial activities were tested for their Escherichia coli FabH inhibitory activity. Especially, compound E9 showed the most potent antibacterial activity with MIC values of 0.39-1.56 μg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC(50) of 2.5 μM. Docking simulation was performed to position compound E9 into the E. coli FabH active site to determine the probable binding conformation.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.forename: Yan-Bin
authors.initials: YB
authors.lastname: Zhang
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Tang
authors.forename: Yu-Shun
authors.initials: YS
authors.lastname: Yang
authors.forename: Ruo-Qi
authors.initials: RQ
authors.lastname: Chen
authors.forename: Fei
authors.initials: F
authors.lastname: Zhang
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects / Q000254:growth & development; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054889:Fatty Acid Synthase, Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D041681:NIH 3T3 Cells; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D014641:Vanillic Acid / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D006835:Hydrazones; D000123:Acetyltransferases; C557158:fabH protein, E coli; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D054889:Fatty Acid Synthase, Type II; D014641:Vanillic Acid