摘要
目的设计合成截短侧耳素衍生物,寻找广谱、高效、安全的新化合物。方法以天然产物截短侧耳素为起始原料,合成3个氨基苯醚类截短侧耳素衍生物和8个氨基酸取代的苯基醚类截短侧耳素衍生物,并进行活性测试、初步成药性评价以及分子对接研究。结果设计合成了11个未见文献报道的新型截短侧耳素衍生物,其结构经核磁、ESI-MS和HRMS确证。大多数化合物对标准金黄色葡萄球菌和标准大肠埃希菌的抗菌活性均优于lefamulin,并且其细胞毒活性低(IC50>10μmol/L),理化性质预测良好。分子对接结果表明,化合物侧链连接的氨基苯醚与氨基酸能够与结合空腔的核苷酸形成更多的氢键相互作用。结论氨基苯酚以及氨基酸的修饰有助于提高截短侧耳素类抗生素的抗菌活性和理化性质。
Objective The objective of this study was to design and synthesize pleuromutilin derivatives in order to discover new compounds that exhibit broad-spectrum antibacterial activity,high efficiency,and safety.Methods The starting material used for the synthesis of the pleuromutilin derivatives was the natural product pleuromutilin.Three aminophenyl ether pleuromutilin derivatives and eight amino acid substituted phenyl ether pleuromutilin derivatives were synthesized.Activity tests,preliminary druggability evaluations,and molecular docking studies were conducted.Results Eleven novel pleuromutilin derivatives were designed and synthesized.The structures of these derivatives were confirmed using NMR,ESI-MS,and HRMS.Most of the compounds exhibited better antibacterial activity against standard Staphylococcus aureus and standard Escherichia coli compared to lefamulin.Additionally,these compounds demonstrated low cytotoxic activity(IC50>10μmol/L)and their physicochemical properties were accurately predicted.The results of the molecular docking studies indicated that the aminophenyl ether and amino acid modifications in the side chains of the compounds enabled the formation of more hydrogen bond interactions with the nucleotides in the binding cavity.Conclusion The modification of pleuromutilin antibiotics with aminophenols and amino acids was beneficial in improving their antibacterial activity and physicochemical properties.
作者
向进
罗新宇
张文轩
潘卫东
吴松
Xiang Jin;Luo Xinyu;Zhang Wenxuan;Pan Weidong;Wu Song(School of Pharmaceutical Sciences/State Key Laboratory of Functions and Applications of Medicinal Plants,Guizhou Medical University,Guiyang 550025;Natural Products Research Center of Guizhou Province and Chinese Academy of Sciences,Guiyang 550014;State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing 100050)
出处
《中国抗生素杂志》
CAS
CSCD
北大核心
2024年第1期46-56,共11页
Chinese Journal of Antibiotics
基金
中国医学科学院医学健康与创新项目(No.2021-12M-1-069)。
关键词
截短侧耳素
天然产物结构修饰
抗菌活性
分子对接
细胞毒活性
Pleuromutilin
Structure modification of natural products
Antibacterial activity
Molecular docking
Cytotoxic activity
