去甲基大环内酯类：4,8,10-三去甲基头孢罗红霉素的合成与评价
Desmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin.
作者信息
Wagh Bharat, Paul Tapas, Debrosse Charles, Klepacki Dorota, Small Meagan C, Mackerell Alexander D, Andrade Rodrigo B
机构信息
Department of Chemistry, Temple University, Philadelphia, PA 19122.
Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607.
出版信息
ACS Med Chem Lett. 2013 Nov 14;4(11):1114-1118. doi: 10.1021/ml400337t.
Antibiotic-resistant bacteria are emerging at an alarming rate in both hospital and community settings. Motivated by this issue, we have prepared desmethyl (i.e., replacing methyl groups with hydrogens) analogues of third-generation macrolide drugs telithromycin (TEL, ) and cethromycin (CET, ), both of which are semi-synthetic derivatives of flagship macrolide antibiotic erythromycin (). Herein, we report the total synthesis, molecular modeling, and biological evaluation of 4,8,10-tridesmethyl cethromycin (). In MIC assays, CET analogue was found to be equipotent with TEL () against a wild-type strain, more potent than previously disclosed desmethyl TEL congeners , , and , but fourfold less potent than TEL () against a mutant A2058G strain.
抗生素耐药菌在医院和社区环境中都正以惊人的速度出现。受此问题的推动，我们制备了第三代大环内酯类药物泰利霉素（TEL）和赛托霉素（CET）的去甲基类似物（即用氢取代甲基），这两种药物都是旗舰大环内酯类抗生素红霉素的半合成衍生物。在此，我们报告了4,8,10 - 三去甲基赛托霉素（）的全合成、分子建模及生物学评价。在最低抑菌浓度（MIC）测定中，发现CET类似物对野生型菌株的活性与TEL（）相当，比先前公开的去甲基TEL同系物、和更有效，但对突变型A2058G菌株的活性比TEL（）低四倍。
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