title: Discovery of vinylogous carbamates as a novel class of β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors.
abstract: β-ketoacyl-acyl carrier protein synthase III (FabH) catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase in most bacteria. The important role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of new FabH inhibitors. We first used a structure-based approach to develop 24 new vinylogous carbamates (4a-15a, 4b-15b) that target FabH for the development of new antibiotics in this paper. Potent FabH inhibitory and selective anti- Gram-negative bacteria activities were observed in most of these vinylogous carbamates. Especially, compound 6a and 7a showed the most potent FabH inhibitory activity with IC₅₀ of 2.6 and 3.3 μM, respectively. Docking simulation was performed to position compound 6a into the Escherichia coli FabH active site and the possible binding conformation of compounds has been proposed. The biological data and molecular docking indicated that compounds 6a and 7a were potent inhibitors of E. coli FabH as antibiotics deserving further research.
authors: College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China. huanqiuli@suda.edu.cn
authors: Huan-Qiu
authors: HQ
authors: Li
authors: Yin
authors: Y
authors: Luo
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*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000201:enzymology; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002219:Carbamates; D004791:Enzyme Inhibitors; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase