title: Nonpeptidic Amphiphilic Xanthone Derivatives: Structure-Activity Relationship and Membrane-Targeting Properties.
abstract: 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 (1.56-3.125 μ/mL) and lower hemolytic activity (80.2 μg/mL for 3a versus 19.7 μg/mL for 2c). Compound 3a displayed a membrane selectivity of 25.7-50.4. 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.
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore , 119074 Singapore.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Koh
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.|School of Chemistry and Chemical Engineering, South China University of Technology , Guangzhou 510641, China.
authors.forename: Hanxun
authors.initials: H
authors.lastname: Zou
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.|School of Chemistry and Chemical Engineering, South China University of Technology , Guangzhou 510641, China.
authors.forename: Shuimu
authors.initials: S
authors.lastname: Lin
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.
authors.forename: Huifen
authors.initials: H
authors.lastname: Lin
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.
authors.forename: Rui Ting
authors.initials: RT
authors.lastname: Soh
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.
authors.forename: Fang Hui
authors.initials: FH
authors.lastname: Lim
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.
authors.forename: Wee Luan
authors.initials: WL
authors.lastname: Koh
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.|Bioinformatics Institute (A*STAR) , 30 Biopolis Street, 07-01 Matrix, 138671 Singapore.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.|SRP Neuroscience and Behavioural Disorders, Duke-NUS Graduate Medical School , 169857 Singapore.
authors.forename: Rajamani
authors.initials: R
authors.lastname: Lakshminarayanan
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.|Bioinformatics Institute (A*STAR) , 30 Biopolis Street, 07-01 Matrix, 138671 Singapore.|School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, 637551 Singapore.|Department of Biological Sciences, National University of Singapore , 14 Science Drive 4, 117543 Singapore.
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.affiliation: Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore , 119074 Singapore.|Singapore National Eye Centre , 11 Third Hospital Avenue, 168751 Singapore.
authors.forename: Donald T H
authors.initials: DT
authors.lastname: Tan
authors.affiliation: School of Chemistry and Chemical Engineering, South China University of Technology , Guangzhou 510641, China.
authors.forename: Derong
authors.initials: D
authors.lastname: Cao
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.|SRP Neuroscience and Behavioural Disorders, Duke-NUS Graduate Medical School , 169857 Singapore.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Beuerman
authors.affiliation: Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore.|SRP Neuroscience and Behavioural Disorders, Duke-NUS Graduate Medical School , 169857 Singapore.
authors.forename: Shouping
authors.initials: S
authors.lastname: Liu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003315:Cornea / Q000166:cytology / Q000187:drug effects; D015195:Drug Design; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008566:Membranes / Q000187:drug effects*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D044004:Xanthones; D000255:Adenosine Triphosphate