Goetschi E, Angehrn P, Gmuender H, Hebeisen P, Link H, Masciadri R, Nielsen J
Pharma Division, F. Hoffmann-La Roche LTD, Basel, Switzerland.
Pharmacol Ther. 1993 Nov;60(2):367-80. doi: 10.1016/0163-7258(93)90017-8.
Cyclothialidine is a new, potent DNA gyrase inhibitor isolated from Streptomyces filipinensis. However, it exhibits hardly any growth-inhibitory activity against intact bacterial cells. To explore its potential with regard to the development of a new type of antibacterial, a flexible synthetic route was worked out (i) to investigate the structural requirements for DNA gyrase inhibition and (ii) to search for congeners exerting antibacterial activity. The structure of cyclothialidine was confirmed by total synthesis. Marked DNA gyrase inhibitory activity was found for a number of analogs, a common feature of them being the bicyclic 12-membered lactone bearing one phenolic hydroxy group. Congeners of cyclothialidine were found to exhibit a moderate, but broad-spectrum, in vitro activity against Gram-positive bacteria. Therefore, the DNA gyrase inhibitory principle contained in cyclothialidine can be considered as the basis for a new class of antibacterial agents.
环硫噻啶是从菲律宾链霉菌中分离出的一种新型强效DNA回旋酶抑制剂。然而，它对完整的细菌细胞几乎没有生长抑制活性。为了探索其在新型抗菌药物开发方面的潜力，设计了一条灵活的合成路线：（i）研究抑制DNA回旋酶的结构要求；（ii）寻找具有抗菌活性的类似物。通过全合成确定了环硫噻啶的结构。发现许多类似物具有显著的DNA回旋酶抑制活性，它们的一个共同特征是带有一个酚羟基的双环12元内酯。环硫噻啶的类似物对革兰氏阳性菌表现出中等但广谱的体外活性。因此，环硫噻啶中所含的DNA回旋酶抑制原理可被视为一类新型抗菌剂的基础。
