Synthesis and evaluation of cyclic chalcones as monoamine oxidase inhibitors
Abstract
Parkinson’s disease (PD) is the second most-prevalent age-related neurodegenerative disorder following Alzheimer’s disease. The manifestation of clinical PD begins after a loss of neurons from the substantia nigra pars compacta (SNpc) which lead to the striatal dopamine (DA) deficiency and dysregulation of the motor circuits that project throughout the basal ganglia. The classical PD symptoms are bradykinesia, rigidity and tremor while non-motor symptoms such as dementia, psychosis, depression and apathy also occur. The majority of the population affected by PD is in the aged group over 65 years.
To date, there is no known cure for PD except for the symptomatic relief of motor symptoms using a variety of therapies such as levodopa (L-3,4-dihydroxyphenylanine or L-Dopa), DA agonists and monoamine oxidase B (MAO-B) inhibitors. These therapeutic agents are often used in combination to ensure effective alleviation of symptoms. However, due to adverse effects arising from combined therapies, research into monotherapies for PD is on-going. Amongst others the MAO enzymes, especially the MAO-B isoform, are of particular interest for PD therapy.
MAO (A and B) enzymes are flavin adenine dinucleotide (FAD) dependent enzymes found in the outer mitochondrial membrane of neuronal, glial and other mammalian cells where they catalyse the oxidative deamination of neurotransmitters. MAO-B is predominant in the basal ganglia where it metabolises DA to yield hydrogen peroxide and aldehydes. These compounds may lead to the accumulation of the hydroxyl radical, formed via the Fenton reaction. Therefore, the inhibition of MAO-B may increase physiological DA levels in the brain and may act as neuroprotector against hydroxyl radicals and oxidative stress. Apart from DA and tyramine, which are metabolised by both MAO isoforms, MAO-B is also responsible for the metabolism of other neurotransmitters such as benzylamine and 2-phenylethylamine. MAO-A on the other hand, selectively breaks down amines such as noradrenalin, adrenalin and serotonin, hence MAO-A is a target for other disorders such as anxiety and depression. It is noteworthy that irreversible inhibitors of MAO-A can pose toxicological threats when combined with serotonin drugs and tyramine rich food diets resulting in the serotonin syndrome and “cheese effect”, respectively. Irreversible MAO inhibitors (especially isoform non-selective inhibitors) may pose undesirable risks. For example, selective irreversible MAO-B inhibitors such as selegiline and rasagiline show good inhibitory MAO activities at low doses although isoform selectivity is lost at high or repeated administration. Thus application of selective reversible MAO-B inhibitors is recommended for PD therapy.
Chalcones have recently attracted attention as potential MAO inhibitors for PD therapy. A study by Chimenti and colleagues (2009) reported promising activities of chalcones as inhibitors of MAO-B with the most potent compound displaying an IC50 of 0.0044 μM. This compound also exhibited high isoform selectivity (SI > 11364) in favour of MAO-B. In addition, Robinson, and co-workers (2013) examined the MAO inhibition activity of furanochalcones. The most active compound exhibited an IC50 value of 0.174 μM for the inhibition of MAO-B and 28.6 μM for the inhibition of MAO-A. The results demonstrate that these furan substituted chalcones exhibited moderate to good inhibitory activities towards MAO-B, but showed weak or no inhibition of the MAO-A enzyme. Based on the validity of chalcones as potential MAO-B selective inhibitors, this study will explore structure-activity relationships (SARs) of cyclic chalcones, which are conformational restricted forms of chalcones. In this regard, the study will focus on the 2-benzylidene-1-tetralone class of compounds with various substituents (polar and lipophilic) on rings A and B. SARs will also explore 2-heteroarylidene-1-tetralone derivatives and the effects of these substitutions on the MAO inhibition activities. The open chain chalcone will also be compared to the cyclic tetralone derivatives. This is based on the consideration that restricted analogues are envisaged to, at least, retain the activity and to have better isoform selectivity compared to “open-ring” chalcones.
Chemistry: The cyclic (benzylidenes and heteroarylidenes) along with the open-chain chalcone analogues were studied as three separate series and were synthesised via the Claisen-Schmidt reaction. Depending on the chemical behaviour of the reactants in solution, the reactions were carried out in the presence of either an acid (concentrated hydrochloric acid) or a base (potassium/sodium hydroxide or piperidine) as catalysts. The precipitates obtained by addition of water were dried and recrystallised from appropriate solvents. Chemical characterisation of the structures consisted of nuclear magnetic resonance spectroscopy (NMR) and high resolution mass spectroscopy (HRMS), whereas purities in the range 96–100% (with exception of two compounds; 1d of series 1 at 87.5% and 2c of series 2 at 89.4%) were confirmed by high performance liquid chromatography (HPLC). MAO inhibition studies: The inhibition potencies of the test inhibitors of the three different series were expressed as IC50 values from which the selectivity index (SI) values were determined. The measurement of IC50 values was done by employing the recombinant human enzymes and kynuramine as the substrate. The first series studied the MAO inhibition properties of benzylidene-substituted indanones, tetralones, benzosuberones, chromones, chromanones and thiochromanones. The results indicated that the compounds are moderate inhibitors of MAO with significant selectivity for the MAO-B isoform. The series consisted of 8 compounds, of which 5 exhibited IC50 values below 1 μM, while one inhibitor 1h showed no activity for either MAO isoforms. Compound 1b (a chromone) exhibited the most potent inhibition activity (IC50 = 0.157 μM) and is isoform specific for MAO-B. With regards to the MAO-A isoform, low inhibition potencies were recorded for the series with the most potent inhibitor, 1f (an indanone), exhibiting an IC50 value of 0.346 μM, with a poor isoform selectivity of 0.822. It was concluded that ring expansion to bigger enone rings reduces MAO activity. Therefore, the second series focused on 2-benzylidene-1-tetralones (6-membered ring analogues). The tetralones exhibited relatively moderate and selective inhibition of the MAO-B isoform, with 2u being the most potent inhibitor with an IC50 value of 0.0064 μM. Compound 2p, the most potent MAO-A inhibitor in this series, displays an IC50 value of 0.753 μM. Inhibitor 2t possessed the highest selectivity (SI: 787). The last series studied investigated 2-heteroarylidene-1-tetralone derivatives (4). All 12 compounds explored except for 4g (MAO-A specific) showed selective inhibition for MAO-B. Amongst the 2-heteroarylidene-1-tetralone derivatives, the non-aromatic cyclohexyl ring (4a) yielded relatively potent MAO-B inhibition (IC50 0.895 μM), which is the highest inhibition activity towards MAO-B in the series. Contrary to that, the 2-chloro-3-pyridine derivative (4g) was the most potent and selective MAO-A inhibitor of the series with an IC50 value of 1.37 μM. This makes it a potential drug for the treatment of depression. It was also observed that non-aromatic ring expansion from cyclopentane (4b) to cyclohexane (4a) improves MAO activity significantly.
It may be concluded that this study successfully synthesised series of cyclic chalcone derivatives and recorded promising MAO inhibition activities for many of the compounds. Selective and potent MAO-B inhibitors, in particular, may find application in the treatment of PD
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