Synthesis and physicochemical characterization of acyl myricetins as potential anti-neuroexocytotic agents

Acyl myricetins (monopropionyl-, dipropionyl-, and monooctanoyl-myricetin, termed as MP(1), MP(2), and MO(1), respectively) were synthesized through enzymatic or non-enzymatic esterification reaction of myricetin aglycone. Structure study indicated the hydroxyl group at C4′ in B-ring was highly susceptible to acylation. Over its parental myricetin, acylated compounds showed enhanced lipophilicity (from 7.4- to 26.3-fold) and oxidative stability (from 1.9- to 3.1-fold) on the basis of logP and decay rate, respectively. MO(1), presenting the physicochemical superiority compared to the others, provided lowest EC(50) value of 2.51 μM on inhibition of neutrotransmitter release and CC(50) value of 59.0 μM, leading to widest therapeutic window. All myricetin esters did not show any irritation toxicity when assessed with a chicken embryo assay. This study describes information on acylation of myricetin that has not yet been explored, and suggests that MO(1) has membrane fusion-arresting and anti-neuroexocytotic potential for industrial application due to its enhanced biological properties.