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.

Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4′-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase

“…[30][31][32] We are currently working along such a research line and the results will be presented in due course. The purity of all the intermediates, checked by 1 H NMR and HPLC, was always better than 90%.…”

Benzouracil–coumarin–arene conjugates as inhibiting agents for chikungunya virus

“…55 The Standard Procedure 1 was followed by use of 4 (500.4 mg, 2.376 mmol, 1.0 equiv) in acetone (15 mL), K2CO3 (492.6 mg, 3.564 mmol, 1.5 equiv), and benzenesulfonyl chloride (5a, 503.5 mg, 2.851 mmol, 1.2 equiv). After workup, the residue was purified by use of gravity column chromatography on silica gel (20% EtOAc in hexanes) to give the desired coumarin 6a (728.1 mg, 1.996 mmol) in 84% yield as white solids.…”

Catalytic Amine Oxidation under Ambient Aerobic Conditions: Mimicry of Monoamine Oxidase B

“…[5] There are two isozymes of MAO: MAO-A and MAO-B.W hile the flavin active sites are identical, each form displays ad ifferent substrate and inhibitor profile,a nd the mechanistic basis of this selectivity unknown. [6] 2 Hprimary kinetic isotope (KIE) effects have been observed for the C À Hb ond cleavage step(s) with both MAOA and B. In principle,r ate-contributing cleavage may be envisaged as proceeding by either H + -, H À -, or HC-transfer mechanisms (Scheme 1).…”