Monoamine oxidase inhibition by indanone and benzoquinone analogues
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Parkinson’s disease (PD) is a neurological disorder of which aging is the greatest risk factor. Over the next fifteen years, the number of persons affected by PD worldwide is expected to increase from 4.6 million to 9.3 million. Although PD is not fatal, it seriously inhibits a patient’s quality of life. PD is a debilitating, incurable disease of which only symptomatic treatment is available. In PD the nigrostriatal neuronal pathway degenerates leading to central dopamine deficiency, primarily in the striatal area. Symptoms of PD only present when 70-80% of dopamine in the brain has deteriorated. Levodopa, the metabolic precursor of dopamine, is the first-line treatment of PD. Unlike dopamine, which is primarily metabolised in the periphery, levodopa is able to cross the blood-brain barrier where it is metabolised to yield dopamine in the brain. This replenishes dopamine levels and results in relief of PD symptoms. Unfortunately levodopa is extensively metabolised in the periphery, which reduces its efficacy and for this reason, levodopa is combined with medications that inhibit its metabolism in the periphery. An alternative approach is to combine levodopa with medications that block the metabolism of dopamine, thereby increasing the central dopamine levels after levodopa treatment. The monoamine oxidase (MAO) enzymes are key dopamine metabolising enzymes in the brain and MAO inhibitors are thus used as adjuncts to levodopa in PD therapy. These enzymes consist of two isoforms, namely MAO A and MAO B, which are 70% identical on the amino acid sequence level. In spite of their similarity the MAOs have unique substrate specificities and are thus targets for different disease states. For example, inhibitors of MAO A have been employed as antidepressant agents since MAO A is a major metabolic enzyme of serotonin in the brain. MAO B inhibitors are used in PD therapy since MAO-B is the major metabolic enzyme of dopamine in the brain. It has also been found that many PD patients present with undiagnosed depression and that the dual inhibition of both MAO A and MAO B may be of enhanced value in the treatment of PD. Based on the limited availability of drugs approved for the symptomatic treatment of PD, there exists a need for new therapies for PD. This thesis therefore aims to contribute in this regard by investigating the potential MAO inhibitory potencies of four chemical classes. New effective MAO inhibitors may represent candidates for the treatment of PD. For the purpose of this thesis, selected compounds of each class were synthesised or in some instances obtained from commercial sources, and their respective IC50 values for the inhibition of the human MAOs were determined in vitro. For selected compounds the modes of inhibition (e.g. competitive) and the reversibility of inhibition were examined. The reversibility of inhibition is an important consideration in the design of MAO inhibitors, especially MAO A inhibitors. It has been found that the irreversible inhibition of MAO A in the periphery may lead to a severe and potentially fatal side effect, termed the “cheese reaction”. Irreversible MAO A inhibition blocks the metabolism of dietary tyramine (found in foods such as cheese) leading to increased systemic concentrations of tyramine. Since tyramine is a sympathomimetic amine, the result is a dangerous increase in blood-pressure. Reversible inhibitors, on the other hand, do not cause tyramine-induced changes in blood-pressure, since the inhibitors can be displaced from enzyme binding sites as substrate concentration increases. The first article focused on the synthesis of 1-indanones substituted on the C5 and C6 positions. Also included is a related series of indane derivatives. This study found that these compounds are high potency MAO inhibitors with a selectivity preference towards MAO B. The most potent inhibitors were the series of 1-indanones substituted on the C6 position. These compounds exhibited IC50 values ranging from 0.001-0.030 μM for the inhibition of MAO B and 0.032-1.348 μM for the inhibition of MAO A. Although the 1-indanones and indanes were selective inhibitors of MAO B, a number of compounds, such as 6-(4-chlorobenzyloxy)-2,3-dihydro-1H-inden-1-one (A) may be classified as dual MAO inhibitors. This compound inhibits MAO A and MAO B with IC50 values of 0.032 μM and 0.002 μM, respectively. Further investigation showed that selected 1-indanones are reversible and competitive inhibitors of the MAOs, however, 1-indanones may possibly display tight-binding towards MAO B. The second article investigated the human MAO inhibitory properties of a series of benzoxathiolones derivatives, which are structurally related to the 1-indanones. It was found that the benzoxathiolones are also high potency inhibitors of MAO B with IC50 values ranging from 0.003 to 0.051 μM. 6-(4-Chlorobenzyloxy)-1,3-benzoxathiol-2-one (B) is an example of a dual inhibitor with IC50 values of 0.189 μM for the inhibition of MAO A and 0.003 μM for the inhibition of MAO B. As with the 1-indanones, selected benzoxathiolones were found to be reversible and competitive inhibitors of the MAOs. The third article investigated the MAO inhibition properties of 1,4-naphthoquinone derivatives. This study is based on a literature report that 2,3,6-trimethyl-1,4-naphthoquinone, isolated from flue cured tobacco leaves, is a non-specific MAO inhibitor. The most potent inhibitor of the present study was 5,8-dihydroxy-1,4-naphthoquinone (C) with an IC50 value of 0.860 μM for the inhibition of MAO B. Another compound, shikonin (D), which is a component of chinese herbal medicine, was found to be a dual inhibitor with IC50 values of 1.5 μM and 1.01 μM for the inhibition of MAO A and MAO B, respectively. Interestingly this compound was also previously investigated for cancer therapy. Literature suggests that MAO inhibitors are not only useful in PD and depression, but may find application in cancer and congestive heart failure. By mechanisms of DNA intercalation and MAO inhibition, 1,4-naphthoquinones may be of particular relevance in PD. In the fourth article of this thesis, a series of 1,4-benzoquinone derivatives were synthesised and evaluated as MAO inhibitors. This thesis found the 1,4-benzoquinone compounds are moderate inhibitors of both MAOs. These derivatives inhibit MAO A and MAO B with IC50 values of 5.03-13.2 μM and 3.69-23.2 μM for MAO A and MAO B, respectively. Although these compounds are not considered to be highly potent MAO inhibitors, these inhibition potencies are still similar to clinically used inhibitors such as toloxatone, a MAO A inhibitor. An interesting finding was that in contrast to the 1,4-naphthoquinone compounds, 1,4-benzoquinones bind irreversibly to MAO A. This is the first report of irreversible inhibition for MAO by a quinone compound. This thesis proposes that 1,4-benzoquinones react with a nucleophile within the MAO A active site, thereby modifying the enzyme covalently. The reduced flavin cofactor may act as such a nucleophile. This thesis therefore discovered a number of new MAO inhibitors from four chemical classes. Using molecular modelling, in certain instances, important insights were gained into the binding modes of these inhibitors to the active sites of the MAOs. In addition, useful structure-activity relationships of MAO inhibition by the selected classes of inhibitors were derived. Of particular note is that, among 1-indanone and benzoxathiolone analogues are compounds that inhibit both MAOs. Such compounds may thus find application in the treatment of PD patients also presenting with depression. This thesis thus contributes to the discovery of new MAO inhibitors, compounds that are relevant in the treatment of PD.
- Health Sciences