Parkinson’s disease is an age-related neurodegenerative disorder. The major symptoms of
Parkinson’s disease are closely linked to the pathology of the disease. The main pathology
of Parkinson’s disease consists of the degeneration of neurons of the substantia nigra pars
compacta (SNpc), which leads to reduced amounts of dopamine in the brain. One of the
treatment strategies in Parkinson’s disease is to conserve dopamine by inhibiting the
enzymes responsible for its catabolism. The monoamine oxidase (MAO) B isoform
catalyses the oxidation of dopamine in the central nervous system and is therefore an
important target for Parkinson’s disease treatment. Inhibition of MAO-B provides
symptomatic relief for Parkinson’s disease patients by increasing endogenous dopamine
levels as well as enhancing the levels of dopamine after administration of levodopa (L-dopa),
the metabolic precursor of dopamine.
Recent studies have shown that phthalide can be used as a scaffold for the design of
reversible MAO inhibitors. Although phthalide is a weak MAO-B inhibitor, substitution on the
C5 position of phthalide yields highly potent reversible MAO-B inhibitors. In the present
study, sesamol and benzodioxane were used as scaffolds for the design of MAO inhibitors.
The structures of sesamol and benzodioxane closely resemble that of phthalide, which
suggests that these moieties may be useful for the design of MAO inhibitors. This study may
be viewed as an exploratory study to discover new scaffolds for MAO inhibition. Since
substitution at C5 of phthalide with a benzyloxy side chain yielded particularly potent MAO
inhibitors, the sesamol and benzodioxane derivatives possessed the benzyloxy substituent
in the analogous positions to C5 of phthalide. These were the C5 and C6 positions of
sesamol and benzodioxane, respectively.
The sesamol and benzodioxane derivatives were synthesised by reacting sesamol and 6-
hydroxy-1,4-benzodioxane, respectively, with an appropriate alkyl bromide in the presence
of potassium carbonate (K2CO3) in N,N-dimethylformamide (DMF). 6-Hydroxy-1,4-
benzodioxane, in turn, was synthesised from 1,4-benzodioxan-6-carboxaldehyde. The
structures of the compounds were verified with nuclear magnetic resonance (NMR) and
mass spectrometry (MS) analyses, while the purities were estimated by high-pressure liquid
chromatography (HPLC). Sixteen sesamol and benzodioxane derivatives were synthesised.
To determine the inhibition potencies of the synthesised compounds the recombinant human
MAO-A and MAO-B enzymes were used. The inhibition potencies were expressed as the
corresponding IC50 values. The results showed that the sesamol and benzodioxane
derivatives are highly potent and selective inhibitors of MAO-B and to a lesser extent MAOA.
The most potent MAO-B inhibitor was 6-(3-bromobenzyloxy)-1,4-benzodioxane with an
IC50 value of 0.045 μM. All compounds examined displayed selectivity for the MAO-B
isoform over MAO-A. Generally the benzodioxane derivatives were found to be more potent
inhibitors of human MAO-A and MAO-B than the sesamol derivatives.
The reversibility and mode of MAO-B inhibition of a representative derivative, 6-(3-
bromobenzyloxy)-1,4-benzodioxane, was examined by measuring the degree to which the
enzyme activity recovers after dialysis of enzyme-inhibitor complexes, while Lineweaver-
Burk plots were constructed to determine whether the mode of inhibition is competitive.
Since MAO-B activity is completely recovered after dialysis of enzyme-inhibitor mixtures, it
was concluded that 6-(3-bromobenzyloxy)-1,4-benzodioxane binds reversibly to the MAO-B
enzyme. The Lineweaver-Burk plots constructed were linear and intersected on the y-axis.
Therefore it may be concluded that 6-(3-bromobenzyloxy)-1,4-benzodioxane is a competitive
MAO-B inhibitor.
To conclude, the C6-substituted benzodioxane derivatives are potent, selective, reversible
and competitive inhibitors of human MAO-B. These compounds are therefore promising
leads for the future development of therapy for Parkinson’s disease. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2015
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/15218 |
| Date | January 2014 |
| Creators | Engelbrecht, Idalet |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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