State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Hankou Road, Nanjing 210093, PR China.
ChemMedChem. 2013 Mar;8(3):433-41. doi: 10.1002/cmdc.201200587. Epub 2013 Feb 7.
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-2H-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 μM(-1) against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with an IC(50) value of 1.6 μM. Docking simulation was performed to position compound 10 into the E. coli FabH active site to determine the probable binding conformation.
脂肪酸生物合成在细菌生存中起着至关重要的作用，已经确定该生物合成途径中涉及的几种关键酶是开发新抗菌剂的有吸引力的靶标。在这些有前途的靶标中，β-酮酰基-酰基载体蛋白（ACP）合酶 III（FabH）是最有吸引力的靶标，它可以触发脂肪酸生物合成的起始，并且在革兰氏阳性菌和阴性菌中高度保守。设计具有 FabH 抑制活性的小分子化合物对于开发抗生素药物具有重要意义，这些抗生素药物应该具有高度选择性、低毒性和广谱性。在本手稿中，设计并合成了一系列新型席夫碱化合物，并评估了它们作为潜在抑制剂的生物活性。在这 21 种新化合物中，（E）-N-((3,4-二氢-2H-苯并[b][1,4]二恶庚烷-7-基)亚甲基)十六烷-1-胺（10）显示出最强的抗菌活性，对测试的细菌菌株的 MIC 值为 3.89-7.81 μM(-1)，并显示出最强的大肠杆菌 FabH 抑制活性，IC(50)值为 1.6 μM。进行了对接模拟，将化合物 10 定位到大肠杆菌 FabH 活性部位，以确定可能的结合构象。
