Kitagawa Hideo, Kumura Ko, Takahata Sho, Iida Maiko, Atsumi Kunio
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
Bioorg Med Chem. 2007 Jan 15;15(2):1106-16. doi: 10.1016/j.bmc.2006.10.012. Epub 2006 Oct 13.
Bacterial FAS provides essential fatty acids for use in the assembly of key cellular components. Among them, FabI is an enoyl-ACP reductase which catalyzes the final and rate-limiting step of bacterial FAS. It is a potential target for selective antibacterial action, because it shows low overall sequence homology with mammalian enzymes. Until today, various compounds have been reported as inhibitors of bacterial FabI-inhibitory compounds. To discover novel small-molecular FabI inhibitors, we initially screened our compound library for inhibitory activity toward FabI of Escherichia coli. And discovered 4-pyridone derivatives as a lead compound. Structure optimization studies yielded 4-pyridone derivatives 7n having strong FabI-inhibitory and antibacterial activities against Staphylococcus aureus. There have been no reports concerning 4-pyridone derivatives as FabI inhibitor.
细菌脂肪酸合成酶（FAS）为关键细胞成分的组装提供必需脂肪酸。其中，FabI是一种烯酰-ACP还原酶，催化细菌FAS的最后一步及限速步骤。它是选择性抗菌作用的潜在靶点，因为它与哺乳动物酶的整体序列同源性较低。迄今为止，已有多种化合物被报道为细菌FabI抑制剂。为发现新型小分子FabI抑制剂，我们最初在化合物库中筛选对大肠杆菌FabI的抑制活性。并发现4-吡啶酮衍生物作为先导化合物。结构优化研究得到了对金黄色葡萄球菌具有强FabI抑制和抗菌活性的4-吡啶酮衍生物7n。尚无关于4-吡啶酮衍生物作为FabI抑制剂的报道。
