Discovering Potent Inhibitors Against the β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ) of Helicobacter pylori: Structure-Based Design, Synthesis, Bioassay, and Crystal Structure Determination

• Published in: Journal of medicinal chemistry Vol. 52; no. 8; pp. 2465 - 2481
• Main Authors: He, Lingyan, Zhang, Liang, Liu, Xiaofeng, Li, Xianghua, Zheng, Mingyue, Li, Honglin, Yu, Kunqian, Chen, Kaixian, Shen, Xu, Jiang, Hualiang, Liu, Hong
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.04.2009; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Crystallography, X-Ray; Helicobacter pylori - drug effects; Helicobacter pylori - enzymology; Hydrazines - chemical synthesis; Hydrazines - chemistry; Hydrazines - pharmacology; Hydro-Lyases - antagonists & inhibitors; Hydro-Lyases - chemistry; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Models, Molecular; Pharmacology & Pharmacy; Resorcinols - chemical synthesis; Resorcinols - chemistry; Resorcinols - pharmacology; Science & Technology; Solubility; Structure-Activity Relationship; FATTY-ACID BIOSYNTHESIS; GASTRITIS; DOCKING; RESISTANCE; MECHANISMS; MODEL; UNIDENTIFIED CURVED BACILLI
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8015602

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 IC50 values less than 2 μM. 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 (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.