title: 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.
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.
authors: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona, 4, I-70125 Bari, Italy.
authors: Leonardo
authors: L
authors: Pisani
authors: Maria
authors: M
authors: Barletta
authors: Ramon
authors: R
authors: Soto-Otero
authors: Orazio
authors: O
authors: Nicolotti
authors: Estefania
authors: E
authors: Mendez-Alvarez
authors: Marco
authors: M
authors: Catto
authors: Antonellina
authors: A
authors: Introcaso
authors: Angela
authors: A
authors: Stefanachi
authors: Saverio
authors: S
authors: Cellamare
authors: Cosimo
authors: C
authors: Altomare
authors: Angelo
authors: A
authors: Carotti
mesh_terms: D001572:Benzofurans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase; C105430:benzofuran