Benzofuran-type constituents from the roots of Eupatorium chinense and their MAO-B inhibitory activity

Seven compounds were identified as:12,13-dihydroxyeuparin (1), euparin (2), euparone (3), 6-acetyl-7-hydroxy-2,3-dimethylchromone (4), 3β,6-hydroxytremetone (5), (2R,3S)-5-acetyl-6-hydroxy-2-isopropenyl-3-ethoxy-2,3-dihydrobenzofuran (6), and 1-[(2R,3S)-3-ethoxy-2,3-dihydro-6-hydroxy-2-(1-methylethenyl)-1-benzofuran-5-yl]ethanone (7). Using 12,13-dihydroxyeuparin (1), the major constituent from the roots, as the lead compound, 13 derivatives were synthesized via dihydroxyl acetylation, phenolic hydroxyl benzylation, and carbonyl Aldol condensation.

All synthetic products were confirmed by ¹H NMR, ¹³C NMR, and LC-MS. The MAO-B inhibitory activities of the seven isolated compounds and 13 synthetic derivatives were evaluated using a fluorescence-based assay, with selegiline as the positive control (IC50 = 7 ± 0.86 μM). Among the natural compounds, compound 4 (chromone) exhibited the most potent activity (IC50 = 3 ± 0.65 μM), approximately 2.3-fold more potent than selegiline.

The benzylated derivatives 2b–7b showed improved activity compared with the parent compound 1, with the p -bromobenzyl-substituted derivative 7b displaying the best activity (IC50 = 11 ± 0.27 μM). Structure–activity relationship analysis indicated that the chromone scaffold is a promising MAO-B inhibitory core, the free hydroxyl groups at C-12/C-13 are critical pharmacophores, and the introduction of a bromobenzyl group at the C-7 position significantly enhances MAO-B inhibitory activity.