The evaluation of 1-tetralone and 4-chromanone derivatives as inhibitors of monoamine oxidase
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ORIGINAL ARTICLE
The evaluation of 1‑tetralone and 4‑chromanone derivatives as inhibitors of monoamine oxidase Stephanus J. Cloete1 · Clarina I. N’Da1 · Lesetja J. Legoabe1 · Anél Petzer1,2 · Jacobus P. Petzer1,2 Received: 27 May 2020 / Accepted: 11 September 2020 © Springer Nature Switzerland AG 2020
Abstract Monoamine oxidase (MAO) is of much clinical relevance, and inhibitors of this enzyme are used in the treatment for neuropsychiatric and neurodegenerative disorders such as depression and Parkinson’s disease. The present study synthesises and evaluates the MAO inhibition properties of a series of 33 1-tetralone and 4-chromanone derivatives in an attempt to discover high-potency compounds and to expand on the structure–activity relationships of MAO inhibition by these classes. Among these series, eight submicromolar MAO-A inhibitors and 28 submicromolar MAO-B inhibitors are reported, with all compounds acting as specific inhibitors of the MAO-B isoform. The most potent inhibitor was a 1-tetralone derivative (1h) with I C50 values of 0.036 and 0.0011 µM for MAO-A and MAO-B, respectively. Interestingly, with the reduction of 1-tetralones to the corresponding alcohols, a decrease in MAO inhibition potency is observed. Among these 1-tetralol derivatives, 1p (IC50 = 0.785 μM) and 1o (IC50 = 0.0075 μM) were identified as particularly potent inhibitors of MAO-A and MAO-B, respectively. Potent compounds such as those reported here may act as leads for the future development of MAO-B specific inhibitors. Graphic abstract The present study describes the MAO inhibitory activities of a series of 1-tetralone and 4-chromanone derivatives. Numerous high-potency MAO-B specific inhibitors were identified.
Keywords 1-Tetralone · 4-Chromanone · Monoamine oxidase · Inhibition · Parkinson’s disease
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-020-10143-w) contains supplementary material, which is available to authorised users. * Jacobus P. Petzer [email protected] Extended author information available on the last page of the article
The monoamine oxidase (MAO) enzymes are of much clinical interest since they metabolise neurotransmitter and dietary amines in the peripheral and central tissues [1]. Amine substrates undergo MAO-catalysed deamination to yield an aldehyde, ammonia (or a substituted amine) and hydrogen
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peroxide as products. Two MAO isoforms which are products of distinct genes are expressed in mammalian tissues, MAO-A and MAO-B. These two isoforms are approximately 70% similar on the amino acid sequence level [2, 3]. Considerable overlap in substrate specificities occurs between MAO-A and MAO-B, and dopamine, adrenaline, noradrenaline and tyramine are substrates for both isoforms [4]. In contrast, serotonin is a MAO-A specific substrate, while the arylalkylamines, benzylamine and 2-phenylethylamine are specific substrates for MAO-B. Since inhibitors of MAO-A reduce the central catabolism of serotonin (and
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