GlaxoSmithKline Research Centre Zagreb Ltd, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
Bioorg Med Chem. 2010 Sep 1;18(17):6569-77. doi: 10.1016/j.bmc.2010.06.048. Epub 2010 Jul 3.
Two series of clarithromycin and azithromycin derivatives with terminal 6-alkylquinolone-3-carboxylic unit with central ether bond in the linker were prepared and tested for antimicrobial activity. Quinolone-linker intermediates were prepared by Sonogashira-type C(6)-alkynylation of 6-iodo-quinolone precursors. In the last step, 4'' site-selective acylation of 2'-protected macrolides was completed with the EDC reagent, which selectively activated a terminal, aliphatic carboxylic group in dicarboxylic intermediates. Antimicrobial activity of the new series of macrolones is discussed. The most potent compound, 4''-O-{6-[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydroquinolin-6-yl)-propoxy]-hexanoyl}-azithromycin (10), is highly active against bacterial respiratory pathogens resistant to macrolide antibiotics and represents a promising lead for further investigation.
制备了带有末端 6-烷基喹诺酮-3-羧酸单元和连接子中环醚键的两种克拉霉素和阿奇霉素衍生物系列，并对其进行了抗菌活性测试。喹诺酮-连接子中间体通过 6-碘喹诺酮前体的 Sonogashira 型 C(6)-炔基化反应制备。在最后一步中，使用 EDC 试剂完成 2'-保护的大环内酯的 4'' 位选择性酰化，该试剂选择性地激活二羧酸中间体中的末端脂肪族羧酸基团。讨论了新系列大环内酯的抗菌活性。最有效的化合物 4''-O-{6-[3-(3-羧基-1-乙基-4-氧代-1,4-二氢喹啉-6-基）-丙氧基]-己酰基}-阿奇霉素（10）对对抗生素耐药的细菌呼吸道病原体具有高度活性，是进一步研究的有前途的先导化合物。
