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

• Published in: Journal of medicinal chemistry 2013-03, Vol.56 (6), p.2651-2664
• Main Authors: Pisani, Leonardo, Barletta, Maria, Soto-Otero, Ramon, Nicolotti, Orazio, Mendez-Alvarez, Estefania, Catto, Marco, Introcaso, Antonellina, Stefanachi, Angela, Cellamare, Saverio, Altomare, Cosimo, Carotti, Angelo
• Format: Article
• Language: English
• Subjects: Benzofurans - chemistry; Benzofurans - metabolism; Benzofurans - pharmacology; Drug Discovery; Humans; Molecular Docking Simulation; Monoamine Oxidase - chemistry; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - metabolism; Monoamine Oxidase Inhibitors - pharmacology; Protein Conformation; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4000769

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.