Synthesis of xanthone derivatives with extended pi-systems as alpha-glucosidase inhibitors: insight into the probable binding mode.
A series of novel xanthone derivatives with extended pi-systems, that is, benzoxanthones 2-4, and their structurally perturbed analogs 5-9 have been designed and synthesized as alpha-glucosidase inhibitors. Their inhibitory activities toward yeast's alpha-glucosidase were evaluated with the aim to enrich the structure-activity relationship. The results indicated that benzoxanthones 2-4 were capable of inhibiting in vitro yeast's alpha-glucosidase 17- to 28-fold more strongly than xanthone derivative 1 that has smaller conjugated pi-system. Benzoxanthone 8, bearing angularly fused aromatic rings, and reduced benzoxanthone 5 showed decreased activities, strongly suggesting that linearly conjugated pi-systems play a crucial role in the inhibition process. O-Methylation of 3-OH of benzoxanthone 2 and nitration at C4 position led to a large decrease in the activity. This indicates that 3-OH of benzoxanthone was crucial to the inhibitory activity, primarily as an H-bonding donor. The present results suggest that pi-pi stacking effect and H-bonding make substantial contributions to elicit the inhibitory activities of this general class of inhibitors.
Liu
Yan
Y
School of Chemistry & Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
Ma
Lin
L
Chen
Wen-Hua
WH
Wang
Bo
B
Xu
Zun-Le
ZL
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007202:Indicators and Reagents; D014970:Xanthines