文献类型：期刊文献

中文题名：抗耐药铜绿假单胞菌DK2增敏剂的结构优化与活性评价

英文题名：Structural modification and activity evaluation of sensitizers against drug-resistant Pseudomonas aeruginosa DK2

作者：曾茹[1];陆淘淘[1,2];吴铃钰[1];张庆[1];石东磊[1];李剑[1,2];宋施豪[1];刘文文[1];李宝力[1]

机构：[1]海南大学药学院热带生物资源教育部重点实验室,海口海南570228;[2]华东理工大学药学院,上海200237

年份：2023

卷号：40

期号：12

起止页码：1587

中文期刊名：沈阳药科大学学报

外文期刊名：Journal of Shenyang Pharmaceutical University

收录：CSTPCD;;北大核心:【北大核心2020】；CSCD:【CSCD_E2023_2024】；

基金：国家自然科学基金青年基金(22107023)。

语种：中文

中文关键词：铜绿假单胞菌DK2;多粘菌素B;增敏剂;苯甲酰胺类;结构优化

外文关键词：Pseudomonas aeruginosa DK2;polymyxin B;sensitizer;benzamide;structural modification

摘要：目的发现有效增敏多粘菌素B抗耐药铜绿假单胞菌DK2,并且具有良好安全性和水溶性的化合物。方法将本课题组前期所发现的先导化合物B4进行苯甲酰胺类化合物的设计与合成,并且通过微量肉汤稀释法测试目标化合物对铜绿假单胞菌DK2的体外增敏活性,CCK8测试优选目标化合物HEK-293细胞毒性及HPLC法测试优选目标化合物的水溶性。结果合成了19个目标化合物并进行了结构确证及DK2菌株体外增敏活性测定,其中,目标化合物15a和24a在浓度为32μg·mL^(-1)时将多粘菌素B增敏到浓度为1μg·mL^(-1),并且安全性明显优于B4。此外,24a水溶性优于15a,但未优于B4。结论通过结构改造,得到优选目标化合物24a,为后续开发增敏多粘菌素B抗耐药铜绿假单胞菌DK2的候选药物提供了良好的结构基础。
Objective To discovered compounds that effectively sensitize polymyxin B against drug-resistant Pseudomonas aeruginosa DK2,with excellent safety and water solubility.Methods Benzamides were designed and synthesized based on the lead compound B4 discovered previously, followed by in vitro sensitization activity testing against Pseudomonas aeruginosa DK2 using a micro-dilution broth method.The cytotoxicity of the selected compounds were further evaluated in HEK-293 cells using the CCK-8 assay and the water solubility of the chosen were determined compounds were determined through HPLC analysis.Results Nineteen target compounds were synthesized, and their structures were confirmed, along with in vitro sensitizing activity against the Pseudomonas aeruginosa DK2.Among them, compounds 15a and 24a sensitized polymyxin B to 1 μg·mL^(-1) at 32 μg·mL^(-1),with significantly improved safety compared to that of B4.Additionally, compound 24a exhibited better water solubility than 15a but was not superior to B4.Conclusion Through structural modification, the preferred target compound 24a was obtained, providing a solid structural foundation for the subsequent development of candidate drugs for sensitizing polymyxin B against drug-resistant Pseudomonas aeruginosa DK2.