title: Discovering potent inhibitors against the beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ) of Helicobacter pylori: structure-based design, synthesis, bioassay, and crystal structure determination.
abstract: The discovery of HpFabZ inhibitors is now of special interest in the treatment of various gastric diseases. In this work, three series of derivatives (compounds 3, 4, and 5) were designed, synthesized, and their biological activities were investigated as potential HpFabZ inhibitors in a two phased manner. First, we designed and synthesized two series of derivatives (3a-r and 4a-u) and evaluated the enzyme-based assay against HpFabZ. Five compounds (3i-k, 3m, and 3q) showed potential inhibitory activity, with IC(50) values less than 2 muM. Second, a focused combinatorial library containing 280 molecules was designed employing the LD1.0 program. Twelve compounds (5a-l) were selected and synthesized. The activity of the most potent compound 5h (IC(50) = 0.86 muM) was 46 times higher than that of the hit 1. The high hit rate and the potency of the new HpFabZ inhibitors demonstrated the efficiency of the strategy for the focused library design and virtual screening.
authors.affiliation: Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: He
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Liu
authors.forename: Xianghua
authors.initials: X
authors.lastname: Li
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
authors.forename: Kunqian
authors.initials: K
authors.lastname: Yu
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D018360:Crystallography, X-Ray; D016480:Helicobacter pylori / Q000187:drug effects / Q000201:enzymology*; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D012118:Resorcinols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: C540341:3-hydroxynaphthalene-2-carboxylic acid (3,5-dibromo-2,4-dihydroxy-benzylidene)hydrazide; D006834:Hydrazines; D012118:Resorcinols; D006836:Hydro-Lyases; C036180:beta-hydroxyacyl-(acyl-carrier-protein)dehydrase