合成及抗菌评价 13 位取代的小檗碱衍生物作为一类新型抗耐甲氧西林金黄色葡萄球菌药物。

Synthesis and antibacterial evaluation of 13-substituted cycloberberine derivatives as a novel class of anti-MRSA agents.

机构信息

Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

出版信息

Eur J Med Chem. 2018 Sep 5;157:877-886. doi: 10.1016/j.ejmech.2018.08.050. Epub 2018 Aug 18.

DOI:10.1016/j.ejmech.2018.08.050

PMID:30145374

Abstract

A series of new 13-substituted cycloberberine (CBBR) derivatives were prepared and evaluated for their antibacterial activities against Gram-positive bacteria taking CBBR as the lead. Structure-activity relationship revealed that the introduction of a suitable electron-donating group at the 13-position in CBBR might be beneficial for the antibacterial potency. Among them, compounds 5b and 5w exhibited high potency against methicillin-sensitive (MSSA) and resistant strains of S. aureus (MRSA) with MIC values of 1-4 μg/mL. Both of them also displayed high stabilities in blood, and good in vivo safety profiles with LD values of 65.6 and 41.2 mg kg in intravenous route respectively. Molecular docking analysis indicated that compound 5b might target FtsZ protein that could inhibit cell division, with the advantage of activity against multidrug resistant S. aureus. Therefore, we consider 13-substituted CBBR derivatives to be a novel class of anti-MRSA agents worthy of further investigation.

摘要

一系列新型的 13 位取代的小檗碱（CBBR）衍生物被制备出来，并对其进行了抗革兰氏阳性菌活性的评估，以 CBBR 作为先导化合物。构效关系研究表明，在 CBBR 的 13 位引入合适的供电子基团可能有利于提高抗菌活性。其中，化合物 5b 和 5w 对甲氧西林敏感（MSSA）和耐甲氧西林金黄色葡萄球菌（MRSA）具有高活性，MIC 值为 1-4μg/mL。它们在血液中也具有很高的稳定性，并且在静脉途径中具有良好的体内安全性，LD 值分别为 65.6 和 41.2mg/kg。分子对接分析表明，化合物 5b 可能靶向 FtsZ 蛋白，从而抑制细胞分裂，具有抗多重耐药性金黄色葡萄球菌的优势。因此，我们认为 13 位取代的 CBBR 衍生物是一类有前途的新型抗 MRSA 药物，值得进一步研究。