Discovering Potent Inhibitors Against the β-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 enzymebased assay against HpFabZ. Five compounds (3i-k, 3m, and 3q) showed potential inhibitory activity, with IC50 values less than 2 μM. Second, a focused combinatorial library containing 280 molecules was designed employing the LD1.0 program. Twelve compounds (5a-1) were selected and synthesized. The activity of the most potent compound 5h (IC50=0.86 μM) 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.
Lingyan He Hualiang Jiang Hong Liu Liang Zhang Xiaofeng Liu Xianghua Li Mingyue Zheng Honglin Li Kunqian Yu Kaixian Chen Xu Shen
Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of M Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of M
国际会议
武汉
英文
749-765
2010-09-01（万方平台首次上网日期，不代表论文的发表时间）