title: Novel Schiff-base-derived FabH inhibitors with dioxygenated rings as antibiotic agents.
abstract: Fatty acid biosynthesis plays a vital role in bacterial survival and several key enzymes involved in this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Of these promising targets, β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target that could trigger the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Designing small molecules with FabH inhibitory activity displays great significance for developing antibiotic agents, which should be highly selective, nontoxic and broad-spectrum. In this manuscript, a series of novel Schiff base compounds were designed and synthesized, and their biological activities were evaluated as potential inhibitors. Among these 21 new compounds, (E)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methylene)hexadecan-1-amine (10) showed the most potent antibacterial activity with a MIC value of 3.89-7.81 μM(-1) against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with an IC(50) value of 1.6 μM. Docking simulation was performed to position compound 10 into the E. coli FabH active site to determine the probable binding conformation.
authors: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Hankou Road, Nanjing 210093, PR China.
authors: Yang
authors: Y
authors: Zhou
authors: Qian-Ru
authors: QR
authors: Du
authors: Jian
authors: J
authors: Sun
authors: Jing-Ran
authors: JR
authors: Li
authors: Fei
authors: F
authors: Fang
authors: Dong-Dong
authors: DD
authors: Li
authors: Yong
authors: Y
authors: Qian
authors: Hai-Bin
authors: HB
authors: Gong
authors: Jing
authors: J
authors: Zhao
authors: Hai-Liang
authors: HL
authors: Zhu
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D012545:Schiff Bases / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D012545:Schiff Bases; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase