Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin
Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin
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DOI：
10.1021/ml300230h
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发表时间：
2012-12-01
影响因子：
4.2
通讯作者：
Andrade, Rodrigo B.
中科院分区：
文献类型：
--
作者：
Wagh, Bharat;Paul, Tapas;Andrade, Rodrigo B.
迫切需要新的抗生素来源来解决不断出现且不可避免的细菌耐药性问题。为此，我们启动了一项基于结构的药物设计计划，其特点是去甲基化策略（即用氢取代甲基）。在此，我们报告了 4,8-二去甲基泰利霉素 (5) 的全合成、分子建模和生物学评价，这是第三代酮内酯抗生素泰利霉素 (2) 的新型去甲基类似物，泰利霉素是 FDA 批准的红霉素半合成衍生物 (1)。我们发现，在 MIC 测定中，5 的活性比之前制备的 4,8,10-三甲基同源物 (3) 高八倍，比 4,10-二甲基区域异构体 (4) 高两倍。虽然其效力不如泰利霉素 (2)，并且与之前 4,10-二甲基类似物 (4) 研究中的观察结果相似，但包含单个甲基可提高生物活性，从而支持其在抗生素活性中的作用。
There is an urgent need for novel sources of antibiotics to address the incessant and inevitable onset of bacterial resistance. To this end, we have initiated a structure-based drug design program that features a desmethylation strategy (i.e., replacing methyl groups with hydrogens). Herein, we report the total synthesis, molecular modeling, and biological evaluation of 4,8-didesmethyl telithromycin (5), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (2), which is an FDA-approved semisynthetic derivative of erythromycin (1). We found 5 to be eight times more active than previously prepared 4,8,10-tridesmethyl congener (3) and two times more active than 4,10-didesmethyl regioisomer (4) in MIC assays. While less potent than telithromycin (2) and paralleling the observations made in the previous study of 4,10-didesmethyl analogue (4), the inclusion of a single methyl group improves biological activity, thus supporting its role in antibiotic activity.