Design, synthesis and biological evaluation of simplified analogues of MraY inhibitory natural product with rigid scaffold
Design, synthesis and biological evaluation of simplified analogues of MraY inhibitory natural product with rigid scaffold
复制标题
DOI：
10.1016/j.bmc.2021.116556
复制
发表时间：
2022-01-08
影响因子：
3.5
通讯作者：
Ichikawa, Satoshi
中科院分区：
文献类型：
--
作者：
Okamoto, Kazuhiro;Ishikawa, Aoi;Ichikawa, Satoshi
muraymycin和caprazamycin是MraY的强抑制剂，MraY负责肽聚糖的生物合成。虽然它们是一种很有前途的新型抗菌药物，但它们的化学结构相当复杂。本研究通过基于结构的药物设计、合成和生物学评价来研究这些天然产物的简化。我们开发了一种具有芳炔部分的简化刚性支架，其具有亚微摩尔的MraY抑制活性。由于我们的合成策略，该支架适合进一步研究结构-活性关系，其中感兴趣的取代基安装在合成的最后阶段。该支架在优化MraY抑制和抗菌活性方面显示出进一步应用的潜力。
Muraymycins and caprazamycins are strong inhibitors of MraY, which is responsible for peptidoglycan biosynthesis. Although they are promising antibacterial agents with a novel mode of action, their chemical structures are rather complex. This study investigated the simplification of these natural products by structure based drug design, synthesis, and biological evaluation. We developed a simplified rigid scaffold with an arylalkyne moiety, which shows sub-micromolar MraY inhibitory activity. The scaffold is suitable for further investigating the structure-activity relationship by virtue of our synthetic strategy, where the substituent of interest is installed in the last stage of synthesis. This scaffold shows the potential for further use in optimizing MraY inhibitory and antibacterial activities.