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

Citations Over TimeTop 10% of 2013 papers

Abstract

The use of selective inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B) holds a therapeutic relevance in the treatment of depressive disorders and Parkinson's disease (PD), respectively. Here, the discovery of a new class of compounds acting as monoamine oxidase inhibitors (MAO-Is) and bearing a 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) and a pronounced MAO-A/B selectivity. The corresponding 6'-benzyloxy derivatives showed potent MAO-B inhibition and inverted selectivity profile. The rigid E-geometry of the exocyclic double bond allowed a more efficient binding conformation compared to more flexible and less active 2-(1-benzofuran-3-yl)-N-methylacetamide isomers and 4-N-methylcarboxamidomethylcoumarin analogues. Focused structural modifications and docking simulations enabled the identification of key molecular determinants for high affinity toward both MAO isoforms. These novel MAO-Is may represent promising hits for the development of safer therapeutic agents with a potential against depression, PD, and other age-related neurodegenerative pathologies.

Related Papers

• → Moclobemide Response in Depressed Patients: Association Study with a Functional Polymorphism in the Monoamine Oxidase A Promoter(2002)41 cited
• → Mode of action and characteristics of monoamine oxidase-A inhibition by moclobemide(1992)17 cited
• Moclobemide response in depressed patients: Association study with a functional polymorphism in the monoamine oxidase-A promoter(2000)
• The effect of moclobemide, reversible inhibitor of monoamine oxidase-A, on the ethanolized rat brain(2013)
• → Comparison of moclobemide with selective serotonin reuptake inhibitors on sexual function in depression(1999)