Nonpeptidic Amphiphilic Xanthone Derivatives: Structure-Activity Relationship and Membrane-Targeting Properties

作者：Koh, Jun-Jie; Zou, Hanxun; Lin, Shuimu; Lin, Huifen; Soh, Rui Ting; Lim, Fang Hui; Koh, Wee Luan; Li, Jianguo; Lakshminarayanan, Rajamani; Verma, Chandra; Tan, Donald T. H.; Cao, Derong^*; Beuerman, Roger W.^*; Liu, Shouping^*

来源：Journal of Medicinal Chemistry, 2016, 59(1): 171-193.

DOI：10.1021/acs.jmedchem.5b01500

• STAPHYLOCOCCUS-AUREUS MRSA
• ANTIMICROBIAL PEPTIDES
• ALPHA-MANGOSTIN
• NATURAL-PRODUCTS
• ANTIBACTERIAL
• RESISTANCE
• CONJUGATION
• CHALLENGES
• BACTERIA
• DESIGN

We recently reported the bioinspired synthesis of a highly potent nonpeptidic xanthone, 2c (AM-0016), with potent antibacterial activity against MRSA. Herein, we report a thorough structure-activity relationship (SAR) analysis of a series of nonpeptidic amphiphilic xanthone derivatives in an attempt to identify more potent compounds with lower hemolytic activity and greater membrane selectivity. Forty-six amphiphilic xanthone derivatives were analyzed in this study and structurally classified into four groups based on spacer length, cationic moieties, lipophilic chains, and triarm functionalization. We evaluated and explored the effects of the structures on their membrane-targeting properties. The SAR analysis successfully identified 3a with potent MICs (1.563.125 mu/mL) and lower hemolytic activity (80.2 mu g/mL for 3a versus 19.7 mu g/mL for 2c). Compound 3a displayed a membrane selectivity of 25.750.4. Thus, 3a with improved HC50 value and promising selectivity could be used as a lead compound for further structural optimization for the treatment of MRSA infection.

• 出版日期2016-1-14
• 单位华南理工大学