Department of Chemistry, Chemistry Research Laboratory , University of Oxford , 12 Mansfield Road , Oxford OX1 3TA , U.K.
Oxford Antibiotic Group , The Oxford Science Park, Magdalen Centre , Oxford OX4 4GA , U.K.
J Org Chem. 2018 Sep 7;83(17):10303-10317. doi: 10.1021/acs.joc.8b01453. Epub 2018 Aug 10.
Tetramic acids with unsaturated acyl chains are widely found in natural products possessing a range of biological activities, and bicyclic tetramates represent a suitable scaffold to prepare simple mimics of such complex molecules. An efficient route to functionalize the C(6)-acyl group of a bicyclic tetramate was developed and utilized to prepare a small chemical library with a range of saturated and unsaturated side-chains. The analogues with lipophilic residues possessed highly potent antibacterial activity, which was selective for Gram-positive bacteria, and the best compound was 37-fold more potent than the cephalosporin C control and with an appropriate therapeutic window.
具有不饱和酰基链的四氢酸广泛存在于具有多种生物活性的天然产物中，而双环四甲酸盐则代表了制备此类复杂分子简单模拟物的合适支架。开发了一种有效途径来官能化双环四甲酸盐的 C(6)-酰基基团，并利用该途径制备了具有一系列饱和和不饱和侧链的小型化学文库。具有亲脂性残基的类似物具有高效的抗菌活性，对革兰氏阳性菌具有选择性，最佳化合物的活性比头孢菌素 C 对照物高 37 倍，且具有适当的治疗窗口。
