Synthesis and in vitro Evaluation of 2-heteroarylidene-1-tetralone Derivatives as Monoamine Oxidase Inhibitors

Abstract

The present study investigates the human monoamine oxidase (MAO) inhibition properties of a series of twelve 2-heteroarylidene-1-tetralone derivatives. Also included are related cyclohexylmethylidene, cyclopentylmethylidene and benzylidene substituted 1-tetralones. These compounds are related to the 2-benzylidene-1-indanone class of compounds which has previously been shown to inhibit the MAOs, with specificity for the MAO-B isoform. The target compounds were synthesised by the Claisen-Schmidt condensation between 7-methoxy-1-tetralone or 1-tetralone, and various aldehydes, under acid (hydrochloric acid) or base (potassium hydroxide) catalysis. The results of the MAO inhibition studies showed that the 2-heteroarylidene-1-tetralone and related derivatives are in most instances more selective inhibitors of the MAO-B isoform compared to MAO-A. (2E)-2-Benzylidene-7-methoxy-3,4-dihydronaphthalen-1(2 H)-one (IC=0.707 μM) was found to be the most potent MAO-B inhibitor, while the most potent MAO-A inhibitor was (2E)-2-[(2-chloropyridin-3-yl)methylidene]-7-methoxy-3,4-dihydronaphthalen-1(2 H)-one (IC=1.37 μM). The effect of the heteroaromatic substituent on MAO-B inhibition activity, in decreasing order was found to be: cyclohexyl, phenyl>thiophene>pyridine, furane, pyrrole, cyclopentyl. This study concludes that, although some 2-heteroarylidene-1-tetralone derivatives are good potency MAO inhibitors, in general their inhibition potencies, particularly for MAO-B, are lower than structurally related chalcones and 1-indanone derivatives that were previously studied.

Synthesis and Structure Activity Relationships of Chalcone based Benzocycloalkanone Derivatives as Adenosine A1 and/or A2A Receptor Antagonists

“…On the 1 H NMR spectra of the said derivatives the signal of the vinyl proton of the α,βunsaturated carbonyl group was observed at approximately 7.42-7.81 ppm. The same trend was previously observed with the characterization of benzylidene indanones [23,24] and tetralones [25,26,37,38].Theoretically, these derivatives may be either (E)or (Z)-isomers [39]. The (E)-configuration is favourable for thermodynamic reasons, due to steric interaction between the carbonyl and aryl groups in the case of (Z)-isomers [34,39].…”

New Insights on the Activity and Selectivity of MAO-B Inhibitors through In Silico Methods

“…The pharmacophore hypothesis and atom-based 3D-QSAR model were generated using a series of 126 derivatives comprising heteroarylidene-1-indanone [51] (Figure 10a), 2-benzylidene-1-indanone [52] (Figure 10b), benzo[b]tiophen-3-ol [53] (Figure 10c), 2heteroarylidene-1-tetralone derivatives [54] (Figure 10d), C6-and N1-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one [55] (Figure 10e), indanone [56] (Figure 10f), N3/C6disubstituted 4(3H)-quinazolinone [57] (Figure 10g), and C6-and C7-substituted 3,4dihydro-2(1H)-quinolinones [58] (Figure 10h) displaying a wide range of biological activities and selectivities, assessed by biological methods (Table S3).…”

Synthesis and evaluation of C3 substituted chalcone‐based derivatives of 7‐azaindole as protein kinase inhibitors

“…The intermediate was prepared by Friedel-Crafts acylation following a method previously described by Zhang et al (2002), and it was used in the next step without further purification. The target compounds (5a-w) were synthesized in poor to excellent yields (10%-92%) using an acid catalysed aldol condensation method shown in Scheme 1 (Amakali, Legoabe, Petzer, & Petzer, 2018;Nel, Petzer, Petzer, & Legoabe, 2016). Confirmation of synthesis of the target compounds was done by NMR spectroscopic analysis.…”