The evaluation of 1-tetralone and 4-chromanone derivatives as inhibitors of monoamine oxidase

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 IC₅₀ 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. 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; Inhibition; Monoamine oxidase; Parkinson’s disease.

Fig. 1

1-Tetralone (3–4) and 4-chromanone (5–6) compounds that have been reported to act as MAO inhibitors [15, 16, 19]

Fig. 2

Reaction pathway for the synthesis of 1-tetralone derivatives (1a–h), and subsequent reduction to the alcohol derivatives 1i–p. Key: a AlCl₃, toluene, reflux, 1–2 h; b RBr, K₂CO₃, acetone, reflux, 20 h; c NaBH₄, ethanol, reflux, 18 h

Fig. 3

Reaction pathway for the synthesis of 4-chromanone derivatives (2a–q). Key: a CF₃SO₃H, 80 °C, 1.5 h; b 2 N NaOH, 0 °C, 4 h; c RBr, K₂CO₃, acetone, reflux, 20 h

Fig. 4

Examples of sigmoidal plots obtained for the inhibition of MAO-A by 1p (open circles) and MAO-B by 1o (filled circles)

Fig. 5

Reversibility of inhibition of MAO-A (a) and MAO-B (b) by compounds 1p and 1o, respectively. MAO-A was preincubated in the absence of inhibitor (NI—dialysed) and the presence of 1p (1p—dialysed) and pargyline (parg—dialysed), and MAO-B was preincubated in the absence of inhibitor (NI—dialysed) and presence of 1o (1o—dialysed) and (R)-deprenyl (depr—dialysed). After dialysis, the residual enzyme activities were measured. For comparison, the MAO activities of undialysed mixtures of the MAOs and the test inhibitors were also measured (1p/1o—undialysed)

Fig. 6

Lineweaver–Burk plots for the activities of MAO-A (a) and MAO-B (b) in the absence and presence of 1p and 1o, respectively. The insets are replots of the slopes of the Lineweaver-Burk plots versus inhibitor concentration