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

被引：49

作者：

Koh, Jun-Jie ^{[1
,2
]}

Zou, Hanxun ^{[1
,5
]}

Lin, Shuimu ^{[1
,5
]}

Lin, Huifen ^{[1
]}

Soh, Rui Ting ^{[1
,9
]}

Lim, Fang Hui ^{[1
]}

Koh, Wee Luan ^{[1
]}

Li, Jianguo ^{[1
,6
]}

Lakshminarayanan, Rajamani ^{[1
,4
]}

Verma, Chandra ^{[1
,6
,7
,8
]}

Tan, Donald T. H. ^{[2
,3
]}

Cao, Derong ^{[5
]}

Beuerman, Roger W. ^{[1
,4
]}

Liu, Shouping ^{[1
,4
]}

机构：

[1] The Acad, Singapore Eye Res Inst, 20 Coll Rd,Discovery Tower Level 6, Singapore 169856, Singapore

[2] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore 119074, Singapore

[3] Singapore Natl Eye Ctr, 11 Third Hosp Ave, Singapore 168751, Singapore

[4] Duke NUS Grad Med Sch, SRP Neurosci & Behav Disorders, Singapore 169857, Singapore

[5] S China Univ Technol, Sch Chem & Chem Engn, Guangzhou 510641, Guangdong, Peoples R China

[6] Bioinformat Inst A STAR, 30 Biopolis St,07-01 Matrix, Singapore 138671, Singapore

[7] Nanyang Technol Univ, Sch Biol Sci, 60 Nanyang Dr, Singapore 637551, Singapore

[8] Natl Univ Singapore, Dept Biol Sci, 14 Sci Dr 4, Singapore 117543, Singapore

[9] Natl Univ Singapore, Dept Chem, Singapore 117543, Singapore

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 01期

关键词：

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

D O I：

10.1021/acs.jmedchem.5b01500

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：171 / 193

页数：23

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