A Novel Competitive Class of alpha-Glucosidase Inhibitors: (E)-1-Phenyl-3-(4-Styrylphenyl)Urea Derivatives

Abstract

Competitive glycosidase inhibitors are generally sugar mimics that are costly and tedious to obtain because they require challenging and elongated chemical synthesis, which must be stereo-and regiocontrolled. Here, we show that readily accessible achiral (E)-1-phenyl-3-(4-strylphenyl)ureas are potent competitive alpha-glucosidase inhibitors. A systematic synthesis study shows that the 1-phenyl moiety on the urea is critical for ensuring competitive inhibition, and substituents on both terminal phenyl groups contribute to inhibition potency. The most potent inhibitor, compound 12 (IC50 = 8.4 mu m, K-i = 3.2 mu m), manifested a simple slow-binding inhibition profile for alpha-glucosidase with the kinetic parameters k(3) = 0.005256 mu m(-1) min(-1), k(4) = 0.003024 min(-1), and K-i(app) = 0.5753 mu m.