School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
Bioorg Med Chem Lett. 2013 Mar 1;23(5):1387-93. doi: 10.1016/j.bmcl.2012.12.070. Epub 2013 Jan 4.
We report a series of new 9-oxime ether non-ketolides, including 3-hydroxyl, 3-O-acyl and 3-O-alkyl clarithromycin derivatives, and thiophene-containing ketolides 1b-1d. Unlike previously reported ketolide 1a, none of them is comparable to telithromycin. A molecular modeling study was performed to gain insight into the binding mode of alkylides 17-20 with bacterial rRNA and to rationalize the great disparity of their SAR. The 3-O-sidechains of 19 and 20 point to the so-called hydrophilic side of the macrolide ring, as seen in clarithromycin. In contrast, the 3-O-sidechains of 17 and 18 bend to the backside, the so-called hydrophobic side of the macrolide ring. The results clearly indicated the alkylides with improved antibacterial activity might possess a novel binding mode, which is different from clarithromycin and the alkylides with poor activity.
我们报告了一系列新的 9-肟醚非酮内酯，包括 3-羟基、3-O-酰基和 3-O-烷基克拉霉素衍生物，以及含噻吩的酮内酯 1b-1d。与之前报道的酮内酯 1a 不同，它们都不如泰利霉素。进行了分子建模研究，以深入了解烷基化物 17-20 与细菌 rRNA 的结合模式，并合理解释它们 SAR 的巨大差异。19 和 20 的 3-O-侧链指向所谓的克拉霉素中环的亲水侧。相比之下，17 和 18 的 3-O-侧链弯曲到背面，即大环内酯环的所谓疏水侧。结果清楚地表明，具有改善的抗菌活性的烷基化物可能具有不同于克拉霉素和活性差的烷基化物的新型结合模式。
