Parkinson’s disease (PD) is an age-related neurodegenerative disorder. The degeneration of the
neurons of the substantia nigra in the midbrain leads to the loss of dopamine from the striatum, which
is responsible for the motor symptoms of PD. In the brain, the enzyme, monoamine oxidase B (MAOB), An analysis of the Lineweaver-Burk plots indicated that 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-
quinolinone inhibits MAO-B with a Ki value of 2.7 nM. An analysis of the structure-activity
relationships for MAO-B inhibition shows that substitution on the C7 position of the 3,4-dihydro-
2(1H)-quinolinone moiety leads to significantly more potent inhibition compared to substitution on
C6. In this regard, a benzyloxy substituent on C7 is more favourable than phenylethoxy and
phenylpropoxy substitution on this position.
In spite of this, C6-substituted 3,4-dihydro-2(1H)-quinolinone with potent MAO-B inhibitory
activities were also identified. An analyses of selected properties of the 3,4-dihydro-2(1H)-
quinolinones showed that the compounds are highly lipophilic with logP values in the range of 3.03-
4.55. LogP values between 1 and 3 are, however, in the ideal range for bioavailability. The
compounds synthesised have logP values higher than 3, which may lead to lower bioavailability.
Laboratory data further showed that none of the 3,4-dihydro-2(1H)-quinolinones are highly toxic to
cultured cells at the concentrations, 1 μM and 10 μM, tested. For example, the most potent MAO-B
inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, reduced cell viability to 88.11% and
86.10% at concentrations of 1 μM and 10 μM, respectively. These concentrations are well above its
IC50 value for the inhibition of MAO-B. At concentrations required for MAO-B inhibition, the more
potent 3,4-dihydro-2(1H)-quinolinones are thus unlikely to be cytotoxic.
It may thus be concluded that C7-substituted 3,4-dihydro-2(1H)-quinolinones are promising highly
potent and selective MAO-B inhibitors, and thus leads for the therapy of Parkinson’s disease.
represents a major catabolic pathway of dopamine. Inhibitors of MAO-B conserve the depleted
supply of dopamine and are thus used in the therapy of PD. In the present study, a series of 3,4-
dihydro-2(1H)-quinolinone derivatives were synthesized and evaluated as inhibitors of recombinant
human MAO-A and MAO-B. These quinolinone derivatives are structurally related to a series of
coumarin (1-benzopyran-2-one) derivatives, which has been reported to act as MAO-B inhibitors. C6-
and C7-substituted 3,4-dihydro-2(1H)-quinolinone derivatives were synthesized by reacting 6- or 7-
hydroxy-3,4-dihydro-2(1H)-quinolinone with an appropriately substituted alkyl bromide in the
presence of base. To evaluate the MAO inhibitory properties (IC50 values) of the quinolinone
derivatives the recombinant human MAO-A and MAO-B enzymes were used. The reversibility of
inhibition of a representative 3,4-dihydro-2(1H)-quinolinone derivative was examined by measuring
the recovery of enzyme activity after the dilution of the enzyme-inhibitor complexes, while the mode
of MAO inhibition was determined by constructing Lineweaver-Burk plots. To determine the
lipophilicity of the 3,4-dihydro-2(1H)-quinolinone derivatives, the logP values were measured. The
toxicity of the 3,4-dihydro-2(1H)-quinolinone derivatives towards cultured cells (cytotoxicity) was
also measured.
The results document that the 3,4-dihydro-2(1H)-quinolinone derivatives are highly potent and
selective MAO-B inhibitors with most homologues exhibiting IC50 values in the nanomolar range.
The most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, exhibits
an IC50 value of 2.9 nM with a 2750-fold selectivity for MAO-B over the MAO-A isoform. As a
MAO-B inhibitor, this compound is approximately equipotent to the most potent coumarin derivative
(IC50 = 1.14 nM) reported in literature. Since MAO-B activity could be recovered after dilution of
enzyme-inhibitor mixtures, it may be concluded that 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-
quinolinone is a reversible MAO-B inhibitor. The Lineweaver-Burk plots constructed for the
inhibition of MAO-B by 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone were linear and
intersected on the y-axis. These data indicated that this compound also is a competitive MAO-B
inhibitor. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/11189 |
| Date | January 2014 |
| Creators | Meiring, Letitia |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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