Discovery, Biological Evaluation, and Structure鈥揂ctivity and 鈭扴electivity Relationships of 6鈥?Substituted (E)-2-(Benzofuran-3(2H)-ylidene)-N-methylacetamides, a Novel Class of Pot

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• 作者：Leonardo Pisani ; Maria Barletta ; Ramon Soto-Otero ; Orazio Nicolotti ; Estefania Mendez-Alvarez ; Marco Catto ; Antonellina Introcaso ; Angela Stefanachi ; Saverio Cellamare ; Cosimo Altomare ; Angelo Carotti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2651-2664
• 全文大小：502K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

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鈥檚 disease (PD), respectively. Here, the discovery of a new class of compounds acting as monoamine oxidase inhibitors (MAO-Is) and bearing a 6鈥?substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide skeleton is reported. 6鈥?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鈥?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.