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Novel Schiff‐Base‐Derived FabH Inhibitors with Dioxygenated Rings as Antibiotic Agents
Author(s) -
Zhou Yang,
Du QianRu,
Sun Jian,
Li JingRan,
Fang Fei,
Li DongDong,
Qian Yong,
Gong HaiBin,
Zhao Jing,
Zhu HaiLiang
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200587
Subject(s) - docking (animal) , stereochemistry , biochemistry , enzyme , active site , bacteria , antibacterial activity , biosynthesis , acyl carrier protein , fatty acid synthase , antibiotics , escherichia coli , biology , chemistry , gene , medicine , genetics , nursing
Abstract Fatty acid biosynthesis plays a vital role in bacterial survival and several key enzymes involved in this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Of these promising targets, β‐ketoacyl‐acyl carrier protein (ACP) synthase III (FabH) is the most attractive target that could trigger the initiation of fatty acid biosynthesis and is highly conserved among Gram‐positive and ‐negative bacteria. Designing small molecules with FabH inhibitory activity displays great significance for developing antibiotic agents, which should be highly selective, nontoxic and broad‐spectrum. In this manuscript, a series of novel Schiff base compounds were designed and synthesized, and their biological activities were evaluated as potential inhibitors. Among these 21 new compounds, ( E )‐ N ‐((3,4‐dihydro‐2 H ‐benzo[ b ][1,4]dioxepin‐7‐yl)methylene)hexadecan‐1‐amine ( 10 ) showed the most potent antibacterial activity with a MIC value of 3.89–7.81 μ M −1 against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with an IC 50 value of 1.6 μ M . Docking simulation was performed to position compound 10 into the E. coli FabH active site to determine the probable binding conformation.