| dc.description.abstract | Parkinson’s disease is the second most prevalent neurodegenerative disorder after Alzheimer’s disease. Parkinson’s disease is a debilitating, incurable, bradykinetic disorder which seriously inhibits a patient’s quality of life. The aetiology of the disease is still unknown, although it is widely accepted that Parkinson’s disease may be caused by a multifactorial cascade of events. The main pathological hallmark is the degeneration of dopaminergic neurons, mainly in the nigrostriatal pathway of the brain. This degeneration subsequently leads to reduced levels of central dopamine, which give rise to the characteristic symptoms pertaining to movement in Parkinson’s disease. Parkinson’s disease treatment mainly focusses on the elevation of central dopamine levels by either dopamine replacement therapy which consists of either levodopa (L-dopa) and dopamine agonists, or by inhibiting the metabolism of dopamine in the central nervous system through inhibition of either monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT). L-Dopa is still considered the mainstay of Parkinson’s disease treatment, but due to extensive metabolism in the periphery by aromatic-L-amino acid decarboxylase (AADC) and COMT, less than 1% of L-dopa reaches the brain unchanged. By inhibiting these metabolic routes of peripheral L-dopa degradation, L-dopa uptake into the brain can be increased, which subsequently elevates central dopamine levels.
COMT catalyses the metabolism of endogenous catecholamines (such as dopamine) and exogenous compounds with a catechol structure. Through inhibition of peripheral COMT, higher levels of L-dopa can enter the brain for conversion to dopamine. In the brain L-dopa-derived dopamine is metabolically inactivated by MAO through oxidative deamination. Thus, MAO inhibition would serve to elevate central dopamine levels by decreasing the metabolism thereof and may serve to be neuroprotective by decreasing the formation of injurious metabolic by-products. Central dopamine may also be metabolically inactivated by COMT present in the central nervous system. Thus, peripheral as well as central COMT inhibition may be beneficial in the treatment of Parkinson’s disease. Selected metabolic routes of dopamine and the enzymes involved therein will serve as drug targets in this study in order to discover new inhibitors with dual inhibition of MAO and COMT.
Current treatment options available for the management of Parkinson’s disease focus on symptomatic relief with only a limited number of drugs on the market. Thus, there exists a need for new treatment strategies. This thesis will contribute in this regard by synthesising novel compounds and investigating their inhibitory potencies towards MAO and COMT.
Literature reports that chalcones act as potent reversible MAO-B inhibitors. A series of chalcones were thus synthesised in this study and their IC50 values for the inhibition of both isoforms of human MAO (A and B) were determined in vitro. The most potent MAO-B inhibitor was (2E)‐3‐(3‐bromophenyl)‐1‐(3,4‐dihydroxy‐5‐nitrophenyl)prop‐2‐en‐1‐one with an IC50 value of 13.89 μM, while (2E)‐3‐(4‐chlorophenyl)‐1‐(3,4‐dihydroxy‐5‐nitrophenyl)prop‐2‐en‐1‐one was the most potent inhibitor of MAO-A with an IC50 value of 32.37 μM. Since COMT inhibitors currently on the market (tolcapone and entacapone) contain the nitrocatechol moiety, this structural feature was also incorporated into the chalcones synthesised in this study. The chalcones were thus also investigated as potential COMT inhibitors with the aim of discovering compounds with dual inhibition activity towards MAO and COMT. Such compounds are known as multi-target-directed inhibitors and may have enhanced value in the management of Parkinson’s disease. All of the synthesised 3,4-dihydroxy-5-nitrochalcones displayed potent inhibition activity towards rat liver COMT, with the most potent inhibitor, (2E)‐1‐(3,4‐dihydroxy‐5‐nitrophenyl)‐3‐(3‐methoxyphenyl)prop‐2‐en‐1‐one, exhibiting an IC50 value of 0.07 μM. Nine compounds of the synthesised series exhibited mixed MAO and COMT inhibitory activities and can thus be classified as multi-target-directed inhibitors. Such inhibitors may be structurally modified in future studies with the aim of designing more potent multi-target-directed inhibitors.
The MAO inhibitory activities of several naturally occurring compounds have been reported. As a second objective, this thesis evaluated selected commercially available natural compounds with unique structures with the aim to discover novel compounds that may act as multi-target-directed inhibitors of MAO and COMT. The inhibitory potencies of the selected natural compounds for MAO and COMT were determined. The most potent MAO inhibitor among the natural compounds is chrysin which inhibits MAO-A with an IC50 value of 0.77 μM, while an IC50 value 0.79 μM was recorded for MAO-B. The most potent COMT inhibitor among the forty-two natural compounds examined was (+)-catechin with an IC50 value of 0.86 μM. Another natural compound, alizarin, also inhibits COMT with an IC50 value of 0.88 μM. Three of the forty-two tested compounds exhibit dual inhibition of MAO and COMT. These compounds are morin, fisetin and alizarin, and exhibits potent MAO-A inhibition, in addition to acting as COMT inhibitors. Thus, these compounds can be used as leads in the future design of multi-target-directed inhibitors of MAO and COMT. Lastly, our research group has discovered numerous synthetic compounds from various chemical classes which act as potent inhibitors of MAO. These compounds were evaluated in the present study as potential inhibitors of COMT, again with the aim of discovering compounds with dual inhibitory activity towards MAO and COMT. Even though none of the compounds selected for this study inhibited COMT, this study demonstrates the importance of the catechol structure for COMT inhibition | en_US |
