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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
- Source :
- Journal of medicinal chemistry. 56(6)
- Publication Year :
- 2013
-
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 nMIC5049 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.
- Subjects :
- Monoamine Oxidase Inhibitors
biology
Monoamine oxidase
Stereochemistry
Protein Conformation
Stereoisomerism
Molecular Docking Simulation
chemistry.chemical_compound
Structure-Activity Relationship
chemistry
Docking (molecular)
Moclobemide
Drug Discovery
medicine
biology.protein
Molecular Medicine
Structure–activity relationship
Humans
Benzofuran
Monoamine oxidase A
Selectivity
Monoamine Oxidase
medicine.drug
Benzofurans
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 56
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....ac220eced92dc677f6e44eb619d842cd