Discovering potent inhibitors against the beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ) of Helicobacter pylori: structure-based design, synthesis, bioassay, and crystal structure determination.
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.
He
Lingyan
L
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.
Zhang
Liang
L
Liu
Xiaofeng
X
Li
Xianghua
X
Zheng
Mingyue
M
Li
Honglin
H
Yu
Kunqian
K
Chen
Kaixian
K
Shen
Xu
X
Jiang
Hualiang
H
Liu
Hong
H
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
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