Discovery, biological evaluation, and structure-activity and -selectivity relationships of 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-methylacetamides, a novel class of potent and selective monoamine oxidase inhibitors.

摘要: The use of selective inhibitors monoamine oxidase A (MAO-A) and B (MAO-B) holds a therapeutic relevance in the treatment depressive disorders Parkinson’s disease (PD), respectively. Here, discovery new class compounds acting as (MAO-Is) bearing 6′-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide skeleton is reported. 6′-Sulfonyloxy derivatives exhibited outstanding affinities to MAO-A (7.0 nM < IC50 49 nM, much higher than moclobemide) pronounced MAO-A/B selectivity. corresponding 6′-benzyloxy showed potent MAO-B inhibition inverted selectivity profile. rigid E-geometry exocyclic double bond allowed more efficient binding conformation compared flexible less active 2-(1-benzofuran-3-yl)-N-methylacetamide isomers 4-N-methylcarboxamidomethylcoumarin analogues. Focused structural modifications docking simulations enabled identification key molecular determinants for high af...