Evaluation of Selected Natural Compounds as Dual Inhibitors of Catechol-O-Methyltransferase and Monoamine Oxidase.

BACKGROUND: The most effective symptomatic treatment of Parkinson's disease remains the metabolic precursor of dopamine, L-dopa. To enhance the efficacy of L-dopa, it is often combined with inhibitors of the enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) B, key metabolic enzymes of L-dopa and dopamine. OBJECTIVE: This study attempted to discover compounds that exhibit dual inhibition of COMT and MAO-B among a library of 40 structurally diverse natural compounds. Such dual acting inhibitors may be effective as adjuncts to L-dopa and offer enhanced value in the management of Parkinson's disease. METHODS: Selected natural compounds were evaluated as in vitro inhibitors of rat liver COMT and recombinant human MAO. Reversibility of MAO inhibition was investigated by dialysis. RESULTS: Among the natural compounds morin (IC50 = 1.32 µM), chlorogenic acid (IC50 = 6.17 µM), (+)-catechin (IC50 = 0.86 µM), alizarin (IC50 = 0.88 µM), fisetin (IC50 = 5.78 µM) and rutin (IC50 = 25.3 µM) exhibited COMT inhibition. Among these active COMT inhibitors only morin (IC50 = 16.2 µM), alizarin (IC50 = 8.16 µM) and fisetin (IC50 = 7.33 µM) were noteworthy MAO inhibitors, with specificity for MAO-A. CONCLUSION: None of the natural products investigated here are dual COMT/MAO-B inhibitors. However, good potency COMT inhibitors have been identified, which may serve as leads for future development of COMT inhibitors.

Novel monoamine oxidase inhibitors based on the privileged 2-imidazoline molecular framework.

Series of structurally diverse 2-imidazoline derivatives have been synthesized by condensation of substituted aldehydes with ethylenediamine, Pd-catalyzed N-arylation of 2-imidazolines and by the formation of 1,2,4-oxadiazoles and benzoxazepines from 2-imidazoline-containing precursors. The 2-imidazoline derivatives were evaluated as potential inhibitors of human monoamine oxidase (MAO) A and B. Among the 2-imidazolines, good potency inhibitors were discovered with compound 9p (IC50 = 0.012 µM) being the most potent MAO-B inhibitor, while compound 9d (IC50 = 0.751 µM) was the most potent MAO-A inhibitor of the series. These potencies are in the same range as those of reference MAO inhibitors used in the clinic. Among 33 compounds evaluated, 13 exhibited IC50 values in the submicromolar range for the inhibition of an MAO isoform. It is postulated that the imidazoline moieties of some of these inhibitors may be recognized by the imidazoline I2-binding site of MAO. Good potency MAO inhibitors may be useful for the treatment of neuropsychiatric and neurodegenerative disorders such as depression and Parkinson's disease, and future application for the treatment of prostate cancer, congestive heart failure and Alzheimer's disease. In addition, high potency 2-imidazoline-derived MAO inhibitors may be used as potential probes for the imidazoline binding sites of the MAOs, as well as to determine alternative binding regions of imidazoline within the MAO active site.

Nitrocatechol Derivatives of Chalcone as Inhibitors of Monoamine Oxidase and Catechol-O-Methyltransferase.

INTRODUCTION: The efficacy of L-dopa in the treatment of Parkinson's disease depends on its metabolic conversion to dopamine in the brain, however extensive peripheral metabolism of L-dopa diminishes its availability for uptake into the brain. L-Dopa is extensively decarboxylated in the gastrointestinal tract and peripheral tissues by Aromatic L-Amino Acid Decarboxylase (AADC), and AADC inhibitors are thus frequently combined with L-dopa therapy. When AADC is inhibited, 3-Omethylation Catalysed by Catechol-O-Methyltransferase (COMT) becomes a dominant metabolic pathway for L-dopa, and COMT inhibitors may thus also be used as adjuncts to L-dopa in Parkinson's disease. Monoamine Oxidase (MAO), in turn, metabolises dopamine in the brain, and MAO-B inhibitors may exert a dopamine sparing effect in the brain. MATERIALS & METHODS: Based on the roles of COMT and MAO in the metabolism of L-dopa and dopamine, the present study attempts to discover novel dual inhibitors of these enzymes. For this purpose, nitrocatechol derivatives of chalcone were synthesised and evaluated as inhibitors of COMT and MAO. The chalcone class of compounds is well known to potently inhibit MAO-B, while nitrocatechol derivatives (e.g. tolcapone and entacapone) are clinically used COMT inhibitors. RESULTS: The results document that all of the derivatives are high potency in vitro inhibitors of rat liver COMT with IC50 values ranging from 0.07 to 0.29 µM. Under these experimental conditions, tolcapone and entacapone display IC50 values of 0.26 µM and 0.25 µM, respectively. The chalcones are less potent as inhibitors of MAO with the most potent inhibitor possessing a Ki of 4.6 µM for the in vitro inhibition of human MAO-B. CONCLUSION: This study shows that nitrocatechol derivatives of chalcone may act as COMT and MAO-B inhibitors, and proposes a general strategy for further enhancing MAO-B inhibition while retaining the potent COMT inhibition activity of this class.

An investigation of the monoamine oxidase inhibition properties of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives.

Hit, Lead & Candidate Discovery In recent studies, we have shown that pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives act as good potency in vitro inhibitors of the monoamine oxidase (MAO) enzymes. To expand on these series and to further derive structure-activity relationships (SARs) for MAO inhibition, in the present study we synthesized additional homologs and related analogs of these chemical classes. Analyzes of the MAO inhibition properties of the synthesized compounds show that among the pyrrolo[3,4-f]indole-5,7-dione derivatives good potency MAO inhibitors exist as exemplified by 10, which possesses IC50 values for the inhibition of MAO-A and MAO-B of 0.023 and 0.178 µM, respectively. Among thirteen pyrrolo[3,4-f]indole-5,7-diones, nine compounds exhibit IC50 values for the inhibition of an MAO isoform in the submicromolar range. It may be concluded that active MAO inhibitors, such as 10 represent suitable leads for the development of drugs for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. MAO inhibitors are also of interest for the treatment of prostate cancer, certain types of cardiomyopathies and Alzheimer's disease.

The synthesis and evaluation of sesamol and benzodioxane derivatives as inhibitors of monoamine oxidase.

In the present study, series of eight sesamol (1,3-benzodioxol-5-ol) and eight benzodioxane (2,3-dihydro-1,4-benzodioxine) derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The sesamol and benzodioxane derivatives are structurally related to series of phthalide derivatives, which have previously been found to act as potent reversible MAO inhibitors. The results document that the benzodioxane derivatives, in particular, are potent MAO-B inhibitors with IC50 values ranging from 0.045 to 0.947 µM. IC50 values for the inhibition of MAO-B by the homologous series of sesamol derivatives ranged from 0.164 to 7.29 µM. All compounds evaluated are selective for the MAO-B isoform, with IC50 values for the inhibition of MAO-A ranging from 13.2 to >100 µM. It is further shown that for the most potent MAO-B inhibitor, 6-[(3-bromophenyl)methoxy]-2,3-dihydro-1,4-benzodioxine, inhibition is almost completely reversed by dialysis of enzyme-inhibitor mixtures. It may be concluded that benzodioxane derivatives are promising leads for the design of selective MAO-B inhibitors for the treatment of Parkinson's disease.