2-Styrylchromone derivatives as potent and selective monoamine oxidase B inhibitors

A series of eighteen 2-styrylchromone derivatives (see Chart 1) were synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activities. Many of the derivatives inhibited MAO-B comparable to pargyline (a positive control), and most of them inhibited MAO-B selectively. Of the eighteen derivatives, compound 9 having methoxy group at R¹ and chlorine at R⁴ showed both the best MAO-B inhibitory activity (IC₅₀ = 17 ± 2.4 nM) and the best MAO-B selectivity (IC₅₀ for MAO-A/IC₅₀ for MAO-B = 1500). The mode of inhibition of compound 9 against MAO-B was competitive and reversible. Quantitative structure-activity relationship (QSAR) analyses of the 2-styrylchromone derivatives were conducted using their pIC₅₀ values with the use of Molecular Operating Environment (MOE) and Dragon, demonstrating that the descriptors of MAO-B inhibitory activity and MAO-B selectivity were 1734 and 121, respectively, that showed significant correlations (P < 0.05). We then examined the 2-styrylchromone structures as useful scaffolds through three-dimensional-QSAR studies using AutoGPA, which is based on the molecular field analysis algorithm using MOE. The model using pIC₅₀ value indexes for MAO-B exhibited a determination coefficient (R²) of 0.873 as well as a Leave-One-Out cross-validated determination coefficient (Q²) of 0.675. These data suggested that the 2-styrylchromone structure might be a useful scaffold for the design and development of novel MAO-B inhibitors.