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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.
J Med Chem. 2013 Mar 28; 56(6):2651-64.JM

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Pisani L
Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona, 4, I-70125 Bari, Italy.
Barletta M
No affiliation info available
Soto-Otero R
No affiliation info available
Nicolotti O
No affiliation info available
Mendez-Alvarez E
No affiliation info available
Catto M
No affiliation info available
Introcaso A
No affiliation info available
Stefanachi A
No affiliation info available
Cellamare S
No affiliation info available
Altomare C
No affiliation info available
Carotti A
No affiliation info available

MeSH

BenzofuransDrug DiscoveryHumansMolecular Docking SimulationMonoamine OxidaseMonoamine Oxidase InhibitorsProtein ConformationStereoisomerismStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23437843

Citation

Pisani, Leonardo, et al. "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." Journal of Medicinal Chemistry, vol. 56, no. 6, 2013, pp. 2651-64.
Pisani L, Barletta M, Soto-Otero R, et al. 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. J Med Chem. 2013;56(6):2651-64.
Pisani, L., Barletta, M., Soto-Otero, R., Nicolotti, O., Mendez-Alvarez, E., Catto, M., Introcaso, A., Stefanachi, A., Cellamare, S., Altomare, C., & Carotti, A. (2013). 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. Journal of Medicinal Chemistry, 56(6), 2651-64. https://doi.org/10.1021/jm4000769
Pisani L, et al. 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. J Med Chem. 2013 Mar 28;56(6):2651-64. PubMed PMID: 23437843.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Pisani,Leonardo, AU - Barletta,Maria, AU - Soto-Otero,Ramon, AU - Nicolotti,Orazio, AU - Mendez-Alvarez,Estefania, AU - Catto,Marco, AU - Introcaso,Antonellina, AU - Stefanachi,Angela, AU - Cellamare,Saverio, AU - Altomare,Cosimo, AU - Carotti,Angelo, Y1 - 2013/03/13/ PY - 2013/2/27/entrez PY - 2013/2/27/pubmed PY - 2013/5/25/medline SP - 2651 EP - 64 JF - Journal of medicinal chemistry JO - J Med Chem VL - 56 IS - 6 N2 - 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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/23437843/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_ L2 - https://doi.org/10.1021/jm4000769 DB - PRIME DP - Unbound Medicine ER -