| dc.description.abstract | Parkinson’s disease (PD) is the second most common neurodegenerative disease after
Alzheimer’s disease, and it is estimated to affect approximately 1% of the population over the
age of 65. PD is characterised by non-motor and motor symptoms such as resting tremor,
bradykinesia and muscle rigidity, which are a result of neuronal dopamine deficiency due to the
progressive loss of the dopaminergic pathway that leads from the substantia nigra pars
compacta (SNpc) to the striatum. Non-motor symptoms of PD include sleep disturbances,
depression and anxiety.
There is presently no cure for PD, and the present treatment can neither reverse nor stop the
disease progression. However, PD can be treated symptomatically with a variety of therapies
which include L-dopa, dopamine agonists, aromatic L-amino acid decarboxylase (AADC)
inhibitors, catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) B
inhibitors. L-dopa has been the mainstay of PD treatment for over 30 years, and it remains the
most effective treatment to date. However, L-dopa should be combined with a peripheral AADC
inhibitor to ensure its neuronal bioavailability and to avoid its peripheral side-effects. MAO-B
inhibitors have also been found effective in PD treatment because they enhance brain
dopamine levels in PD, and thus alleviate the symptoms.
The MAO-A and MAO-B enzymes are mitochondrial outer membrane-bound flavoproteins that
catalyse the oxidative deamination of monoamine neurotransmitters dopamine, norepinephrine
and epinephrine. The MAOs are differently distributed in the body, with MAO-A dominating in
the intestines, heart and placenta, while MAO-B dominates in the brain, glial cells in the brain
and liver. Oxidation of dopamine by MAO generates hydrogen peroxide and aldehyde
derivatives, by-products which are potentially neurotoxic. MAO-B inhibitors increase brain
dopamine levels and also reduce levels of hydrogen peroxide and aldehyde derivatives in the
brain, and therefore are neuroprotective in this respect. MAO-A inhibitors are used clinically in
treatment of depression, while MAO-B inhibitors are used as therapy for PD. Selective and
reversible MAO inhibitors are more clinically acceptable because they do not cause the sideeffects
that are associated with irreversible and non-selective MAO inhibition.
The aim of the present study was to explore 4(3H)-quinazolinone as a scaffold for design of
potent and selective MAO-B inhibitors.
The MAO inhibitory potential of quinazolinones has been illustrated in several studies. A study
conducted by Bahadur (1982) revealed that quinazolinones can inhibit MAO activity by as much
as 80%. In their study, Bahadur (1982) discovered that the increase or decrease in MAO
inhibitory activity of quinazolinones depends on the type of substituent, as well as the position at
which it is attached. This is in agreement with similar studies carried out by Rastogi et al. (1972) and Lata et al. (1982). A number of studies have been conducted to evaluate quinazolinones as
potential MAO inhibitors, but none have been done to study the structure-activity relationships
(SARs) with respect to thiobenzyl and benzyloxy substitution. This study expanded on the SARs
of MAO inhibition by quinazolinone derivatives to enable the design of novel potent MAO
inhibitors of this chemical class. Particular attention was given to the benzyloxy and thiobenzyl
derivatives of 4(3H)-quinazolinone.
Chemistry: Two series of compounds were synthesised and evaluated as potential MAO
inhibitors. The thioether (14 compounds), C6 mono- (12 compounds) and N3/C6 disubstituted (9
compounds) derivatives of 4(3H)-quinazolinone were synthesised using standard chemical
procedures. The reactants were suspended in either ethanol or N,N-dimethylformamide (DMF)
in the presence of a base. The products were precipitated with ice-cold water and were
subsequently dried or recrystallised from appropriate solvents. The structures and purities were
confirmed by NMR, MS and HPLC.
MAO inhibition studies: To determine the 50% inhibitory concentration (IC50) values and
selectivity index (SI), a fluorometric assay was carried out employing recombinant human MAOA
and MAO-B as enzyme sources, and kynuramine as substrate. The first series consisted of
14 compounds, 12 of which exhibited good MAO-B inhibition properties, with IC50 values in the
micromolar to sub-micromolar range. The most potent compound in this series (3k) exhibited an
IC50 value of 0.142 μM. Interesting trends were observed through the SAR analyses of the
compounds in this series. For example, meta-halogen substitution of the thioether derivatives
dramatically increased the inhibitor potencies. A number of derivatives (5 of 21) in the second
series showed selective inhibition of MAO-B. The disubstituted compounds 2b and 2h are
notable as the most potent inhibitors in this series with IC50 values of 0.685 μM and 0.847 μM,
respectively. However, meaningful SARs for MAO inhibition could not be derived because most
compounds in this series did not inhibit the MAOs.
The 4(3H)-quinazolinone derivatives were successfully synthesised in this study, and it may be
concluded that they are potent and selective MAO-B inhibitors, thus promising leads for the
future design of PD therapies | en_US |
