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

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.