Parkinson’s disease (PD) is a neurodegenerative disorder, which is progressive in nature and usually associated with the elderly. It is the second most common age-related neurodegenerative disorder after Alzheimer’s disease (AD). PD occurs when there is a dramatic loss of dopamine (DA) in the striatum, a substructure of the basal ganglia, of the brain due to the degeneration of the nigrostriatal pathway that contains the dopaminergic neurons. Motor symptoms of PD include bradykinesia, muscular rigidity and resting tremors. Non-motor symptoms include speech and sleep problems, hallucinations and depression. Diverse treatment options are available to treat the symptoms of PD, including levodopa (L-Dopa), DA agonists and monoamine oxidase B (MAO-B) inhibitors. The MAOs are flavoproteins that are bound to the outer membrane of the mitochondria and catalyze the oxidative deamination of neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and DA. Two isoforms occur, namely MAO-A and –B, which share a 70% sequence identity. MAO-A catalyzes the oxidation of 5-HT and MAO-B has a substrate specificity towards benzylamine and 2-phenylethylamine. DA, NA, adrenaline and tryptamine are oxidized by both forms. MAO-A plays an important role in depression while MAO-B plays an important role in PD. The two isoforms are not evenly distributed in the brain. Of particular relevance to PD is the observation that, in the basal ganglia, MAO-B is the predominant form and the oxidation of DA in this region is largely due to MAO-B activity. Also, with an increase in age, there is an up to fourfold increase in MAO-B activity in the brain. In the aged parkinsonian brain, MAO-B is therefore a major DA metabolizing enzyme and MAO-B inhibitors have an important role in the therapy of PD. MAO-B inhibitors may potentially reduce the metabolic destruction of DA and thereby provide relief from the symptoms of PD. MAO-B inhibitors may also exert a neuroprotective effect in PD. In the catalytic cycle of MAO-B, one mole each of an aldehyde, hydrogen peroxide and ammonia are formed for each mole of primary amine substrate oxidized. Ferrous iron, which is abundant in the basal ganglia, may react with the hydrogen peroxide to form hydroxyl radicals in the Fenton reaction. The hydroxyl radical damages virtually all types of biomolecules including proteins, DNA, lipids, carbohydrates and amino acids. The aldehyde, in turn, may react with amino groups of proteins, and thus lead to cell injury. Inhibitors of MAO-B may reduce the MAO-catalyzed formation of hydrogen peroxide and aldehydes in the basal ganglia, and thus act as neuroprotective agents. MAO-B inhibitors that are currently being used in the treatment of PD are selegiline and rasagiline. Both are irreversible inhibitors of MAO-B. While irreversible inhibitors of MAO have been used extensively as drugs, irreversible inhibition has a number of disadvantages. These include the loss of selectivity as a result of repeated drug administration and a slow and variable rate of enzyme recovery following termination of drug treatment. The turnover rate for the biosynthesis of MAO-B in the human brain may require as much as 40 days while with reversible inhibition, enzyme activity is recovered when the inhibitor is eliminated from the tissues. For these reasons the discovery of novel MAO-B inhibitors, which interact reversibly with the enzymes are of value in the therapy of PD. The goal of this study was to design novel and reversible inhibitors of MAO-B, which may find application in the therapy of PD. In the current study, caffeine was used as scaffold for the design of new MAO inhibitors. Caffeine is reported to be a weak inhibitor of MAO-B, with an IC50 value of 5084 μM. Substitution at C-8 of the caffeine moiety, however, yields compounds with potent MAO-B inhibitory properties. Of particular importance to this study is a recent report that a series of 8-sulfanylcaffeine analogues acts as selective inhibitors of human MAO-B. Among the compounds examined, 8-[(phenylethyl)sulfanyl]caffeine was found to be a particularly potent MAO-B inhibitor with an IC50 value of 0.223 μM. In an attempt to further enhance the MAO-B inhibition potency of 8-[(phenylethyl)sulfanyl]caffeine, and possibly to discover highly potent MAO-B inhibitors, a series of five 8-[(phenylethyl)sulfanyl]caffeine analogues was synthesized and evaluated as inhibitors of human MAO-A and –B. For the purpose of this study 8- [(phenylethyl)sulfanyl]caffeine homologues containing C-3 alkyl (CF3, CH3 and OCH3) and halogen (Cl and Br) substituents on the phenyl ring were considered. Furthermore, a series of two 8-sulfinylcaffeine analogues and one 8-sulfonylcaffeine were synthesized and their MAO inhibitory potencies were measured. The purpose with these compounds was to compare the MAO inhibitory properties of the 8-sulfinylcaffeine analogues and 8-sulfonylcaffeine with those of the 8-sulfanylcaffeine analogues. This study also investigates the MAO inhibition properties of three selected 8-[(phenylpropyl)sulfanyl]caffeine and two 8-(benzylsulfanyl)caffeine analogues. Chemistry: The target 8-sulfanylcaffeine analogues were synthesized according to the literature procedure. 8-Chlorocaffeine was reacted with an appropriate mercaptan in the presence of NaOH, to yield the target 8-sulfanylcaffeine analogues in yields of 6.4–50.7%. 8-Chlorocaffeine, in turn, was conveniently synthesized in high yield by reacting chlorine with caffeine in chloroform. In certain instances, the mercaptan starting materials were not commercially available and were thus synthesized according to the literature procedure by reacting an appropriate alkylbromide with thiourea. The resulting thiouronium salt was hydrolyzed in the presence of NaOH to yield the target mercaptan. The 8-sulfinylcaffeine analogues and 8- sulfonylcaffeine were synthesized by reacting the 8-sulfanylcaffeines with H2O2 in the presence of glacial acetic acid and acetic anhydride. The structures and the purities of the inhibitors were verified by NMR, MS and HPLC analyses. MAO inhibition studies: The MAO inhibitory properties of the test compounds were examined using the recombinant human enzymes. The mixed MAO-A/B substrate, kynuramine, was employed as substrate for both enzymes and the inhibition potencies were expressed as the IC50 values. The 8-[(phenylethyl)sulfanyl]caffeine analogues were found to be highly potent inhibitors of MAO-B. The IC50 values recorded for these homologues ranged from 0.017–0.125 μM, making them twofold to 13-fold more potent MAO-B inhibitors than the lead compound, 8- [(phenylethyl)sulfanyl]caffeine (IC50 = 0.223 μM). For comparison, the reversible MAO-B selective inhibitor, lazabemide, exhibits an IC50 value of 0.091 μM under the same conditions (unpublished data from our laboratory). Interestingly, both alkyl (CF3, CH3 and OCH3) and halogen (Cl and Br) substitution lead to highly potent MAO-B inhibition. It may therefore be concluded that substitution on C-3 is a general strategy to enhance the MAO-B inhibition potency of 8-[(phenylethyl)sulfanyl]caffeine. The results of the MAO inhibitory studies with the 8- [(phenylpropyl)sulfanyl]caffeine analogues showed that these compounds are also inhibitors of MAO-B with IC50 values of 0.061–0.500 μM. Those homologues substituted with chlorine on the para and meta positions of the phenyl ring were found to be exceptionally potent inhibitors with IC50 values of 0.061 μM and 0.062 μM, respectively. For the series of 8- (benzylsulfanyl)caffeines, meta substitution with chlorine (IC50 = 0.227 μM) and bromine (IC50 = 0.199 μM) was also found to enhance the MAO-B inhibition potency of 8- (benzylsulfanyl)caffeine (IC50 = 1.86 μM). The results document that the 8-sulfinylcaffeines are also inhibitors of MAO-B with IC50 values of 11.8–131 μM. The 8-sulfonylcaffeine was also found to be a MAO-B inhibitor. Compared to the 8-sulfanylcaffeines, these homologues are, however, weaker inhibitors. It may, therefore, be concluded that 8-sulfinylcaffeines and 8-sulfonylcaffeines are comparatively weak MAO-B inhibitors and less suited for the design of high potency MAO-B inhibitors. The results also document that the 8-[(phenylethyl)sulfanyl]caffeines are relatively weak MAO-A inhibitors with IC50 values of 5.66–141 μM, with one homologue exhibiting no inhibition under the experimental conditions. As evident from the selectivity indices (SI values), the 8- [(phenylethyl)sulfanyl]caffeines were all selective inhibitors of the MAO-B isoform. Two compounds exhibited SI values in excess of 1000. Since these compounds are also highly potent MAO-B inhibitors, they represent suitable leads for the design of potent and selective MAO-B inhibitors. The 8-sulfinylcaffeines and 8-sulfonylcaffeine were found to be weak MAO-A inhibitors with IC50 values of 166–250 μM. The SI values demonstrate that these compounds are MAO-B selective inhibitors, although to a lesser degree than the 8- [(phenylethyl)sulfanyl]caffeines. The 8-[(phenylpropyl)sulfanyl]caffeines are also MAO-A inhibitors with IC50 values of 0.708–6.48 μM. It is noteworthy that these homologues are the most potent MAO-A inhibitors among the compounds evaluated in this study. In fact, one of the 8-[(phenylpropyl)sulfanyl]caffeines, 8-{[3-(4-chlorophenyl)propyl]sulfanyl}caffeine (IC50 = 0.708 μM), is the only compound with an IC50 value for the inhibition of MAO-A in the submicromolar range. The 8-[(phenylpropyl)sulfanyl]caffeines display, in general, lower degrees of selectivity for MAO-B than the corresponding 8-[(phenylethyl)sulfanyl]caffeines. Reversibility studies: The reversibility of the interaction of a representative inhibitor, 8-{[2-(3- (trifluoromethyl)phenyl)ethyl]sulfanyl}caffeine, with MAO-B was investigated by evaluating the recovery of the enzymatic activity after dilution of the enzyme-inhibitor complex. For this purpose, MAO-B was preincubated with the test compound at concentrations of 10 × IC50 and 100 × IC50 for 30 min. The reactions were subsequently diluted 100-fold to 0.1 × IC50 and 1 × IC50, respectively. The results show that, after dilution to 0.1 × IC50 and 1 × IC50, the MAO-B catalytic activities are recovered to 35% and 22%, respectively, of the control value. For reversible enzyme inhibition, the enzyme activities are expected to recover to levels of approximately 90% and 50%, respectively, after 100-fold dilution of the preincubations containing inhibitor concentrations of 10 × IC50 and 100 × IC50. After preincubation of MAO-B with the irreversible inhibitor (R)-deprenyl (at 10 × IC50), and dilution of the resulting complex to 0.1 × IC50, MAO-B activity is not recovered (3.0% of control). These data indicate that the test compound does indeed react reversibly with MAO-B but because enzyme activities are not recovered to the expected 90% and 50% respectively, it may suggest that the test compound possess a quasi-reversible or tight-binding component. Hansch-type structure activity relationship studies: A limited Hansch-type QSAR study was performed for the inhibition of MAO by the 8-[(phenylethyl)sulfanyl]caffeines. For this purpose, five parameters were used to describe the physicochemical properties of the C-3 substituents on the phenyl rings of the inhibitors. The Van der Waals volume (Vw) and Taft steric parameter (Es) served as descriptors of the bulkiness of the substituents, while the lipophilicities were described by the Hansch constant (π). The electronic properties were described by the classical Hammett constant (σm) and the Swain-Lupton constant (F). A one-parameter fit with the Taft steric parameter versus the inhibition potency (logIC50) yielded the best correlation with a correlation coefficient (R2) of 0.912 and a statistical F value of 41.27 (Fmax = 35). The positive sign of the Es (+0.47) parameter coefficient indicated that the inhibition potencies of the 8- [(phenylethyl)sulfanyl]caffeines towards MAO-B may be enhanced by substitution with sterically large groups at C-3 of the phenyl rings of the inhibitors. / Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013

Aims of this project - The aim of this study was to design and synthesise novel 2-aminopyrimidine derivatives as potential adenosine A1 and A2A receptor antagonists. Background and rationale - Parkinson’s disease is the second most common neurodegenerative disorder (after Alzheimer’s disease) and is characterised by the selective death of the dopaminergic neurons of the nigro-striatal pathway. Distinctive motor symptoms include bradykinesia, muscle rigidity and tremor, while non-motor symptoms, of which cognitive dysfunction is an example, also frequently occur. Current therapy provides symptomatic relief mainly by augmentation of dopaminergic signalling (levodopa, dopamine agonists, MAO and COMT enzyme inhibitors), but disease progression is not adequately addressed. New therapies that can prevent further neurodegeneration in addition to providing symptomatic relief are therefore urgently required. Adenosine has an important function as neuromodulator in the central nervous system. The adenosine A2A receptor in particular plays an essential role in the regulation of movement. This, coupled to the fact that it is uniquely distributed in the basal ganglia, contributes to its attractiveness as non-dopaminergic target in the treatment of movement disorders, such as Parkinson’s disease. The efficacy of adenosine receptor antagonists has been illustrated in animal models of Parkinson’s disease and several adenosine receptor antagonists have also reached clinical trials. The neuroprotective properties of adenosine A2A receptor antagonists are further attributed to their ability to modulate neuro-inflammation and decrease the release of the excitatory neurotransmitter glutamate, which is implicated in neurotoxicity. While adenosine A1 receptor antagonism has a synergistic effect on the motor effects of adenosine A2A receptor antagonism, it has the additional benefit of improving cognitive dysfunction, a cardinal non-motor symptom of Parkinson’s disease. Dual antagonism of adenosine A1 and A2A receptors therefore offers the potential of providing symptomatic relief as well as the neuroprotection so desperately needed in the clinical environment. Amino substituted heterocyclic scaffolds, such as those containing the 2-aminopyrimidine motif, have been shown to exhibit good efficacy as dual adenosine receptor antagonists. Since the structure activity relationships of 2-aminopyrimidines have not been comprehensively explored, it is in this regard that this study aimed to make a contribution. Results - Fourteen 2-aminopyrimidines were synthesised successfully over three steps, (although in low yields) and characterised by nuclear magnetic resonance and infrared spectroscopy, mass spectrometry, by determination of melting points and high performance liquid chromatography. Structure modifications explored included variation of the aromatic substituent on position 4, as well as variations in the substituents of the phenyl ring, present on position 6 of the pyrimidine ring. Radioligand binding assays were performed to determine the affinities of the synthesised compounds for the adenosine A1 and A2A receptor subtypes. Several high dual affinity derivatives were identified during this study; the compound with the highest affinity was 4-(5- methylthiophen-2-yl)-6-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-amine (39f) with Ki values of 0.5 nM and 2.3 nM for the adenosine A2A and adenosine A1 receptors, respectively. A few general structure activity relationships were derived, which included: The effect of the aromatic substituent (position 4) on A2A affinity could be summarised (in order of declining affinity) as follows: 5-methylthiophene > phenyl > furan > pyridine > p-fluorophenyl > benzofuran. On the other hand, the effect of this substituent on A1 receptor affinity could be summarised (in order of declining affinity) as follows: phenyl > 5-methylthiophene > pfluorophenyl > benzofuran > pyridine. The affinities as exhibited by the methylthiophene derivatives 39f, 39h – 39j, further showed that while piperidine substitution (39f) resulted in optimal A2A and A1 affinity, pyrrolidine substitution (39j) was less favourable. Substitution at the 4ʹ position of the phenyl ring, as well as thiazole substitution, generally resulted in poor adenosine A1 and A2A receptor affinity. However, 4-[2-amino-6-(5-methylfuran-2-yl)pyrimidin- 4-yl]-N-(1,3-benzothiazol-2-yl)benzamide (39l) surprisingly demonstrated good affinity and selectivity for the adenosine A1 receptor. The results obtained during radioligand binding assays were rationalised by QSAR and molecular modelling (Discovery Studio 3.1, Accelrys) studies. The inverse relationship seen between log Ki (as indicator of affinity) and polar surface area, illustrated the importance of this physico-chemical property in the design of 2-aminopyrimidine A2A antagonists. The results from the docking study further showed that the orientation adopted by derivatives in the binding cavity (and particular hydrogen bonding to Asn 253 and Glu 169) is of importance. Results from the MTT cell viability assay indicated that none of the high affinity derivatives had a significant effect on cell viability at 1 μM, a concentration much higher than their Ki values. However, incorporation of the furan, benzofuran and p-fluorophenyl groups as aromatic substituent and a pyrrolidine as amine substituent, presented liabilities. Lastly, the haloperidol induced catalepsy assay (in rats) was used to give a preliminary indication of adenosine receptor antagonism or agonism. Compound 39f failed to reverse catalepsy under standard conditions, but showed some reversal after an increased time period. Indications therefore exist that 39f is an adenosine receptor antagonist that suffers from bioavailability issues. Compound (39c), 4-phenyl-6-[3-(piperidine-1- carbonyl)phenyl]pyrimidin-2-amine which also demonstrated promising affinity in the radioligand binding assays however showed a statistically significant reduction in catalepsy, indicating adenosine A2A receptor antagonism, and in vivo efficacy. Highly potent, dual affinity aminopyrimidine derivatives with acceptable toxicity profiles were identified in this study, with compound 39c demonstrating in vivo activity. The aim of designing and synthesising a promising dual adenosine A1/A2A receptor antagonist is therefore realised, with compound 39c as the most favourable example. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

This dissertation examines the relation between embodiment and language, knowledge and memory, as explored in the poetry of South African poet Gabeba Baderoon. In her three published collections of poetry, namely, The Museum of Ordinary Life, The Dream in the Next Body and A Hundred Silences, she depicts seemingly trivial and everyday events or experiences with acute attention to detail, all of which are connected by her unique portrayal of their embodied nature. In doing so, her work illustrates that intellectual activities typically associated with the mind, such as language, knowledge and memory, in fact require the incorporation of the body. Therefore, this dissertation studies the mind-body relation represented in her work with regard to these thematic concerns, since it is a crucial aspect of her poetry and aids not only in understanding and interpreting her work, but also the discourse on embodiment in general. These concerns do, moreover, not remain on a thematic level, but are evident in her poetry itself; that is, her poems too act as a form of embodiment. Furthermore, Baderoon’s poems are able to transcend the supposed mind-body dichotomy in a way that shows much in common with phenomenology, and especially the perspective held by authors such as Maurice Merleau-Ponty. This dissertation incorporates phenomenological ideas on the body and embodiment, as these assist in interpreting Baderoon’s work, as well as for the reason that her poetry sheds new light upon the understanding of such phenomenological ideas, too. Thus, this dissertation seeks to elucidate the manner in which Gabeba Baderoon’s poetry transcends the mind-body dichotomy by means of her exceptional employment of the notion of embodiment on a thematic as well as formal level. / Thesis (MA (English))--North-West University, Potchefstroom Campus, 2012

Studies of MHWs, (social workers, social auxiliary workers, trauma counsellors, and telephone counsellors), who work with trauma and stress, often focus on pathological symptoms and on the need to develop psycho-education programmes (Figley, 2002; Johnson & Hunter, 1997; Mac Ritchie & Leibowitz, 2010; Mikulincer, 1994; Stiles, 2002). A gap was identified how MHWs, who continuously intervene with traumatised children, cope with the stressors associated with their work. The purpose of this research was to explore the coping strategies of Mental Health Workers (MHWs) exposed to Secondary Trauma (ST)as a result of having to deal day to day with children (younger than 18) who have experienced trauma, including sexual, physical and emotional abuse, as well as the witness of violence. The MHWs’ coping responses were investigated using a qualitative case study approach. The investigation showed how MHWs constructed their realities by examining their coping strategies and the individual meanings they assigned to these. A convenience sample, based on the availability of participants, was selected. Nine women and one man, ranging in age from 26 to 57 years, employed at Childline Gauteng, participated in the research. The Mmogo-Method®, a projective visual research technique, explored the MHWs’ coping experiences through qualitative data collection methods. Visual and textual data were gathered and analysed thematically. It was found that the MHWs at Childline Gauteng displayed two main coping styles, namely intrapersonal and relational coping strategies. In the face of their daily stressors, MHWs managed to cope successfully by using strategies that are embedded in their daily activities. Their ability to find alternative ways to cope, despite continuous exposure to children’s trauma, allowed the MHWs to fulfil their work obligations. Their intrapersonal coping strategies reflected an ability to draw on their inner resources. Being aware of their environment and how it affects them, MHWs were able to regulate themselves and their environments by adopting positive attitudes. These attitudes, and the MHWs’ dispositions, positively affected their outlook on life. Moreover, MHWs maintained a healthy distance from their stressful environment by means of meaningful disengagement. Meaningful disengagement was fundamental to creating solitude as a coping strategy. Personal and professional boundaries, self-care and being able to draw on spirituality were further coping resources. MHWs’ discussions about finding meaning in their work revealed that they would not be able to do their work if they did not experience it as spiritually significant. Drawing on external resources, relational coping strategies included supportive relationships with family, friends and colleagues. Reciprocal unconditional acceptance significantly contributed to coping because it was important for MHWs to experience family and friends' attitudes as supportive and non-judgemental. MHWs encountered an organisational culture of care in the form of freedom to interact with colleagues and managers and sharing experiences. This interaction contributed to successful coping because MHWs felt comfort in the knowledge that they were not alone when dealing with children's trauma. This interaction facilitated coping because MHWs were able to interface successfully with their environment, even in difficult circumstances. In conclusion, the MHWs provided nuanced descriptions of the ways in which they experienced coping strategies. They coped with the demands of their profession by using internal and external resources, including intrapersonal and relational coping. / MA (Research Psychology), North-West University, Potchefstroom Campus, 2014

Parkinson’s disease (PD) is a neurodegenerative disorder, which is progressive in nature and usually associated with the elderly. It is the second most common age-related neurodegenerative disorder after Alzheimer’s disease (AD). PD occurs when there is a dramatic loss of dopamine (DA) in the striatum, a substructure of the basal ganglia, of the brain due to the degeneration of the nigrostriatal pathway that contains the dopaminergic neurons. Motor symptoms of PD include bradykinesia, muscular rigidity and resting tremors. Non-motor symptoms include speech and sleep problems, hallucinations and depression. Diverse treatment options are available to treat the symptoms of PD, including levodopa (L-Dopa), DA agonists and monoamine oxidase B (MAO-B) inhibitors. The MAOs are flavoproteins that are bound to the outer membrane of the mitochondria and catalyze the oxidative deamination of neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and DA. Two isoforms occur, namely MAO-A and –B, which share a 70% sequence identity. MAO-A catalyzes the oxidation of 5-HT and MAO-B has a substrate specificity towards benzylamine and 2-phenylethylamine. DA, NA, adrenaline and tryptamine are oxidized by both forms. MAO-A plays an important role in depression while MAO-B plays an important role in PD. The two isoforms are not evenly distributed in the brain. Of particular relevance to PD is the observation that, in the basal ganglia, MAO-B is the predominant form and the oxidation of DA in this region is largely due to MAO-B activity. Also, with an increase in age, there is an up to fourfold increase in MAO-B activity in the brain. In the aged parkinsonian brain, MAO-B is therefore a major DA metabolizing enzyme and MAO-B inhibitors have an important role in the therapy of PD. MAO-B inhibitors may potentially reduce the metabolic destruction of DA and thereby provide relief from the symptoms of PD. MAO-B inhibitors may also exert a neuroprotective effect in PD. In the catalytic cycle of MAO-B, one mole each of an aldehyde, hydrogen peroxide and ammonia are formed for each mole of primary amine substrate oxidized. Ferrous iron, which is abundant in the basal ganglia, may react with the hydrogen peroxide to form hydroxyl radicals in the Fenton reaction. The hydroxyl radical damages virtually all types of biomolecules including proteins, DNA, lipids, carbohydrates and amino acids. The aldehyde, in turn, may react with amino groups of proteins, and thus lead to cell injury. Inhibitors of MAO-B may reduce the MAO-catalyzed formation of hydrogen peroxide and aldehydes in the basal ganglia, and thus act as neuroprotective agents. MAO-B inhibitors that are currently being used in the treatment of PD are selegiline and rasagiline. Both are irreversible inhibitors of MAO-B. While irreversible inhibitors of MAO have been used extensively as drugs, irreversible inhibition has a number of disadvantages. These include the loss of selectivity as a result of repeated drug administration and a slow and variable rate of enzyme recovery following termination of drug treatment. The turnover rate for the biosynthesis of MAO-B in the human brain may require as much as 40 days while with reversible inhibition, enzyme activity is recovered when the inhibitor is eliminated from the tissues. For these reasons the discovery of novel MAO-B inhibitors, which interact reversibly with the enzymes are of value in the therapy of PD. The goal of this study was to design novel and reversible inhibitors of MAO-B, which may find application in the therapy of PD. In the current study, caffeine was used as scaffold for the design of new MAO inhibitors. Caffeine is reported to be a weak inhibitor of MAO-B, with an IC50 value of 5084 μM. Substitution at C-8 of the caffeine moiety, however, yields compounds with potent MAO-B inhibitory properties. Of particular importance to this study is a recent report that a series of 8-sulfanylcaffeine analogues acts as selective inhibitors of human MAO-B. Among the compounds examined, 8-[(phenylethyl)sulfanyl]caffeine was found to be a particularly potent MAO-B inhibitor with an IC50 value of 0.223 μM. In an attempt to further enhance the MAO-B inhibition potency of 8-[(phenylethyl)sulfanyl]caffeine, and possibly to discover highly potent MAO-B inhibitors, a series of five 8-[(phenylethyl)sulfanyl]caffeine analogues was synthesized and evaluated as inhibitors of human MAO-A and –B. For the purpose of this study 8- [(phenylethyl)sulfanyl]caffeine homologues containing C-3 alkyl (CF3, CH3 and OCH3) and halogen (Cl and Br) substituents on the phenyl ring were considered. Furthermore, a series of two 8-sulfinylcaffeine analogues and one 8-sulfonylcaffeine were synthesized and their MAO inhibitory potencies were measured. The purpose with these compounds was to compare the MAO inhibitory properties of the 8-sulfinylcaffeine analogues and 8-sulfonylcaffeine with those of the 8-sulfanylcaffeine analogues. This study also investigates the MAO inhibition properties of three selected 8-[(phenylpropyl)sulfanyl]caffeine and two 8-(benzylsulfanyl)caffeine analogues. Chemistry: The target 8-sulfanylcaffeine analogues were synthesized according to the literature procedure. 8-Chlorocaffeine was reacted with an appropriate mercaptan in the presence of NaOH, to yield the target 8-sulfanylcaffeine analogues in yields of 6.4–50.7%. 8-Chlorocaffeine, in turn, was conveniently synthesized in high yield by reacting chlorine with caffeine in chloroform. In certain instances, the mercaptan starting materials were not commercially available and were thus synthesized according to the literature procedure by reacting an appropriate alkylbromide with thiourea. The resulting thiouronium salt was hydrolyzed in the presence of NaOH to yield the target mercaptan. The 8-sulfinylcaffeine analogues and 8- sulfonylcaffeine were synthesized by reacting the 8-sulfanylcaffeines with H2O2 in the presence of glacial acetic acid and acetic anhydride. The structures and the purities of the inhibitors were verified by NMR, MS and HPLC analyses. MAO inhibition studies: The MAO inhibitory properties of the test compounds were examined using the recombinant human enzymes. The mixed MAO-A/B substrate, kynuramine, was employed as substrate for both enzymes and the inhibition potencies were expressed as the IC50 values. The 8-[(phenylethyl)sulfanyl]caffeine analogues were found to be highly potent inhibitors of MAO-B. The IC50 values recorded for these homologues ranged from 0.017–0.125 μM, making them twofold to 13-fold more potent MAO-B inhibitors than the lead compound, 8- [(phenylethyl)sulfanyl]caffeine (IC50 = 0.223 μM). For comparison, the reversible MAO-B selective inhibitor, lazabemide, exhibits an IC50 value of 0.091 μM under the same conditions (unpublished data from our laboratory). Interestingly, both alkyl (CF3, CH3 and OCH3) and halogen (Cl and Br) substitution lead to highly potent MAO-B inhibition. It may therefore be concluded that substitution on C-3 is a general strategy to enhance the MAO-B inhibition potency of 8-[(phenylethyl)sulfanyl]caffeine. The results of the MAO inhibitory studies with the 8- [(phenylpropyl)sulfanyl]caffeine analogues showed that these compounds are also inhibitors of MAO-B with IC50 values of 0.061–0.500 μM. Those homologues substituted with chlorine on the para and meta positions of the phenyl ring were found to be exceptionally potent inhibitors with IC50 values of 0.061 μM and 0.062 μM, respectively. For the series of 8- (benzylsulfanyl)caffeines, meta substitution with chlorine (IC50 = 0.227 μM) and bromine (IC50 = 0.199 μM) was also found to enhance the MAO-B inhibition potency of 8- (benzylsulfanyl)caffeine (IC50 = 1.86 μM). The results document that the 8-sulfinylcaffeines are also inhibitors of MAO-B with IC50 values of 11.8–131 μM. The 8-sulfonylcaffeine was also found to be a MAO-B inhibitor. Compared to the 8-sulfanylcaffeines, these homologues are, however, weaker inhibitors. It may, therefore, be concluded that 8-sulfinylcaffeines and 8-sulfonylcaffeines are comparatively weak MAO-B inhibitors and less suited for the design of high potency MAO-B inhibitors. The results also document that the 8-[(phenylethyl)sulfanyl]caffeines are relatively weak MAO-A inhibitors with IC50 values of 5.66–141 μM, with one homologue exhibiting no inhibition under the experimental conditions. As evident from the selectivity indices (SI values), the 8- [(phenylethyl)sulfanyl]caffeines were all selective inhibitors of the MAO-B isoform. Two compounds exhibited SI values in excess of 1000. Since these compounds are also highly potent MAO-B inhibitors, they represent suitable leads for the design of potent and selective MAO-B inhibitors. The 8-sulfinylcaffeines and 8-sulfonylcaffeine were found to be weak MAO-A inhibitors with IC50 values of 166–250 μM. The SI values demonstrate that these compounds are MAO-B selective inhibitors, although to a lesser degree than the 8- [(phenylethyl)sulfanyl]caffeines. The 8-[(phenylpropyl)sulfanyl]caffeines are also MAO-A inhibitors with IC50 values of 0.708–6.48 μM. It is noteworthy that these homologues are the most potent MAO-A inhibitors among the compounds evaluated in this study. In fact, one of the 8-[(phenylpropyl)sulfanyl]caffeines, 8-{[3-(4-chlorophenyl)propyl]sulfanyl}caffeine (IC50 = 0.708 μM), is the only compound with an IC50 value for the inhibition of MAO-A in the submicromolar range. The 8-[(phenylpropyl)sulfanyl]caffeines display, in general, lower degrees of selectivity for MAO-B than the corresponding 8-[(phenylethyl)sulfanyl]caffeines. Reversibility studies: The reversibility of the interaction of a representative inhibitor, 8-{[2-(3- (trifluoromethyl)phenyl)ethyl]sulfanyl}caffeine, with MAO-B was investigated by evaluating the recovery of the enzymatic activity after dilution of the enzyme-inhibitor complex. For this purpose, MAO-B was preincubated with the test compound at concentrations of 10 × IC50 and 100 × IC50 for 30 min. The reactions were subsequently diluted 100-fold to 0.1 × IC50 and 1 × IC50, respectively. The results show that, after dilution to 0.1 × IC50 and 1 × IC50, the MAO-B catalytic activities are recovered to 35% and 22%, respectively, of the control value. For reversible enzyme inhibition, the enzyme activities are expected to recover to levels of approximately 90% and 50%, respectively, after 100-fold dilution of the preincubations containing inhibitor concentrations of 10 × IC50 and 100 × IC50. After preincubation of MAO-B with the irreversible inhibitor (R)-deprenyl (at 10 × IC50), and dilution of the resulting complex to 0.1 × IC50, MAO-B activity is not recovered (3.0% of control). These data indicate that the test compound does indeed react reversibly with MAO-B but because enzyme activities are not recovered to the expected 90% and 50% respectively, it may suggest that the test compound possess a quasi-reversible or tight-binding component. Hansch-type structure activity relationship studies: A limited Hansch-type QSAR study was performed for the inhibition of MAO by the 8-[(phenylethyl)sulfanyl]caffeines. For this purpose, five parameters were used to describe the physicochemical properties of the C-3 substituents on the phenyl rings of the inhibitors. The Van der Waals volume (Vw) and Taft steric parameter (Es) served as descriptors of the bulkiness of the substituents, while the lipophilicities were described by the Hansch constant (π). The electronic properties were described by the classical Hammett constant (σm) and the Swain-Lupton constant (F). A one-parameter fit with the Taft steric parameter versus the inhibition potency (logIC50) yielded the best correlation with a correlation coefficient (R2) of 0.912 and a statistical F value of 41.27 (Fmax = 35). The positive sign of the Es (+0.47) parameter coefficient indicated that the inhibition potencies of the 8- [(phenylethyl)sulfanyl]caffeines towards MAO-B may be enhanced by substitution with sterically large groups at C-3 of the phenyl rings of the inhibitors. / Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013

Les intrusions sableuses (ou injectites) sont le plus souvent le produit de la remobilisation post-dépositionnelle des sédiments et de l'injection du sable dans les roches environnantes. Bien que reconnues pour la première fois il y a près de 200 ans, elles ne sont réellement étudiées que depuis quelques dizaines d'années, depuis que les concepts sur les environnements de dépôt dans les domaines marins profonds nous permettent de mieux comprendre les processus de mise en place. Cependant, ces processus restent encore aujourd'hui relativement mal compris. Notre approche repose sur l'étude d'injectites dans le bassin du Bas-Congo a partir de données de sismique et de puits que nous comparerons a un système fossile dans le bassin du SE de la France. Nous avons montre que : (1) Dans des systèmes de chenaux turbiditiques enfouis, les dépôts de drapage sur les marges et terrasses de chenaux présentent la même signature géophysique que les injectites de type "wing". Finalement, le seul critère sismique d'identification des injectites est la présence de réflexions sismiques sécantes vis-a-vis de la stratigraphie associée dans le meilleur des cas au soulèvement des réflecteurs sismiques sus-jacents. (2) Des injectites d'échelle sismique en forme de cône et d'assiette ont été identifiées dans le bassin du Bas-Congo. La remobilisation résulte probablement des pressions anormales induites par l'effet de flottabilité des hydrocarbures piégés dans les marges d'un lobe enfoui sous 160 m de sédiment, puis de l'injection soudaine du sable fluidise associée a la réactivation de failles (possible rôle des diapirs de sel a proximité). (3) Un réseau d'injectites (dykes, sills/wings et laccolites) s'est formé dans le bassin Vocontien entre la fin de l'Albien supérieur et/ou le début du Cénomanien, depuis un chenal turbiditique de l'Albien inférieur-moyen. La mise en place résulte probablement de la compartimentalisation précoce du chenal au cours de son enfouissement et de l'augmentation du taux de sédimentation générant la surpression et de l'apport ulterieur d'importante quantité de fluides profonds déclenchant l'injection. L'injection du sable a été polyphasée : une première injection a formé des sills et une suivante des dykes. Les sills/wings et les dykes se sont propagés latéralement au chenal source sur environ 2 km et vers la surface sur environ 200 m, mettant en évidence une forte remobilisation latérale plutôt que verticale, contrairement a l'idée classiquement admise a partir de l'interprétation des données sismiques. (4) La formation de ce large réseau d'injectites a été gouvernée par des mécanismes d'hydrofracturation. Par conséquent, sa morphologie a été dépendante des hétérogenéités de la roche hôte (milieu isotrope, fracture), des directions de paléo-contraintes (ƒÐ3 = NWSE) et de la profondeur d'enfouissement de la source (300-600 m) au moment de l'injection. L'étude de ce réseau fossile permet de définir les relations entre morphologie du réseau injecté et état de contraintes au moment de l'injection. Cette relation peut être extrapolée de façon à contraindre la morphologie des réseaux de subsurface au-delà de la visibilité sismique. (5) Les sables injectés dans des lithologies de faible perméabilité témoignent d'un épisode d'échappement de fluide important dans les bassins étudiés mais ont aussi guide les fluides longtemps après leur formation. Les injectites contribuent ainsi a l'initiation épisodique et la pérennisation de migrations de fluides dans les bassins sedimentaires. Le processus d'injection est associé a l'échappement brutal de fluides, résultant vraisemblablement d'un évènement tectonique et/ou sédimentaire important, et l'architecture des réseaux d'injectites est gouverné par les paléo-contraintes locales et les hétérogénéités de la roche hôte. Par conséquent, la caractérisation des réseaux d'injectites est une étape importante dans la compréhension de la plomberie des marges, c'est-a-dire l'évolution post-dépôt des bassins sédimentaires.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized pathologically by a marked loss of dopaminergic nigrostriatal neurons and clinically by disabling movement disorders. PD can be treated by inhibiting monoamine oxidase (MAO), specifically MAO–B, since this is a major enzyme involved in the catabolism of dopamine in the substantia nigra of the brain. Inhibition of MAO–B may conserve the dopamine supply in the brain and may therefore provide symptomatic relief for PD patients. Selegiline is an irreversible MAO–B inhibitor and is currently used for the treatment of PD. Irreversible inhibitors inactivate enzymes by forming stable covalent complexes. The process is not readily reversed either by removing the remainder of the free inhibitor or by increasing the substrate concentration. Even dilution or dialysis does not dissociate the enzyme inhibitor complex and restore enzyme activity. From a safety point of view it may therefore be more desirable to develop reversible inhibitors of MAO–B. In this study, caffeine was used as lead compound to design, synthesize and evaluate new reversible inhibitors of MAO–B. This study is based on the finding that C–8 substituted caffeine analogues are potent MAO inhibitors. For example, (E)–8–(3–chlorostyryl)caffeine (CSC) is an exceptionally potent competitive inhibitor of MAO–B with an enzyme–inhibitor dissociation constant (Ki value) of 128 nM. In this study caffeine was similarly conjugated at C–8 to various side–chains. The effect that these chosen side–chains had on the MAO–B inhibition activity of C–8 substituted caffeine analogues will then be evaluated. The caffeine analogues were also evaluated as human MAO–A inhibitors. For the purpose of this study, saturated C–8 side chains were selected with the goal of discovering new C–8 side chains that enhance the MAO–A and ?B inhibition potency of caffeine. As mentioned above, the styryl side chain is one example of a side chain that enhances the MAO–B inhibition potency of caffeine. Should a side chain with promising MAO inhibition activity be identified in this study, the inhibition potency will be further optimized in a future study by the addition of a variety of substituents to the C–8 side chain ring. For example, halogen substitution of (E)–8– styrylcaffeine enhances the MAO–B inhibition potency by up to 10 fold. The saturated side chains selected for the present study included the phenylethyl (1), phenylpropyl (2), phenylbutyl (3) and phenylpentyl (4) functional groups. Also included are the cyclohexylethyl (8), 3–oxo–3– phenylpropyl (5), 4–oxo–4–phenylbutyl (6) moieties. A test compound containing an unsaturated linker between C–8 of caffeine and the side chain ring, the phenylpropenyl analogue 7, was also included. This study is therefore an exploratory study to discover new C–8 moieties that are favorable for MAO– inhibition. All the target compounds were synthesized by reacting 1,3–dimethyl–5,6–diaminouracil with an appropriate carboxylic acid in the presence of a carbodiimide dehydrating agent. Following ring closure and methylation at C–7, the target inhibitors were obtained. Inhibition potencies were determined using recombinant human MAO–A and MAO–B as enzyme sources. The inhibitor potencies were expressed as IC50 values. The most potent MAO–B inhibitor was 8–(5– phenylpentyl)caffeine (4) with an IC50 value of 0.656 ?M. In contrast, all the other test inhibitors were moderately potent MAO–B inhibitors. In fact the next best MAO–B inhibitor, 8–(4– phenylbutyl)caffeine (3) was approximately 5 fold less potent than 4 with an IC50 value of 3.25 ?M. Since the 5–phenylpentyl moiety is the longest side chain evaluated in this study, this finding demonstrates that longer C–8 side chains are more favorable for MAO–B inhibition. Interestingly, compound 5 containing a cyclohexylethyl side chain (IC50 = 6.59 ?M) was approximately 4 fold more potent than the analogue containing the phenylethyl linker (1) (IC50 = 26.0 ?M). This suggests that a cyclohexyl ring in the C–8 side chain of caffeine may be more optimal for MAO–B inhibition and should be considered in future studies. The caffeine analogues containing the oxophenylalkyl side chains (5 and 6) were weak MAO–B inhibitors with IC50 values of 187 ?M and 46.9 ?M, respectively. This suggests that the presence of a carbonyl group in the C–8 side chain is not favorable for the MAO–B inhibition potency of caffeine. The unsaturated phenylpropenyl analogue 7 was also found to be a relatively weak MAO–B inhibitor with an IC50 value of 33.1 ?M. In contrast to the results obtained with MAO–B, the test caffeine analogues were all weak MAOA inhibitors. With the exception of compound 5, all of the analogues evaluated were selective inhibitors of MAO–B. The most potent MAO–B inhibitor, 8–(5–phenylpentyl)caffeine (4) was the most selective inhibitor, 48 fold more potent towards MAO–B than MAO–A. This study also shows that two selected analogues (5 and 3) bind reversibly to MAO–A and ?B, respectively, and that the mode of MAO–A and –B inhibition is competitive for these representative compounds. / Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2011.

This research was conducted to determine what the nature of teachers’ educational beliefs about teaching, knowledge and learning are, whether there is a relation between their educational beliefs and the way in which they instruct, and if a relation exists, what the nature of such a relation is. Teachers’ educational beliefs about the way in which learners learn and what they are supposed to learn, have a major influence on how the teacher instructs and on how the learners achieve. Educational beliefs are a comprehensive phenomenon and include beliefs about everything. Educational beliefs generally refer to beliefs about teaching, knowledge and learning. The construct epistemological beliefs are actually also used in the literature and can be seen as the more restricted construct that only includes beliefs about knowledge and learning. Both constructs are used in this study. The phenomenon of educational beliefs is used concerning the beliefs about teaching, knowledge and learning, whilst the phenomenon of epistemological beliefs are used when concerned with the beliefs about knowledge and learning. Educational beliefs vary from naïve to sophisticated. Teachers are characterised according to their educational beliefs about teaching as more teacher–centered or more learner–centered. Teachers who are more teacher–centered have more naïve epistemological beliefs and promote superficial learning, which leads to lower academic performances. Conversely, teachers who are more learner–centered have more sophisticated epistemological beliefs that promote an in depth approach to learning, which leads to higher academic performances. The implementation of Outcomes Based Education (OBE) requires inter alia a learner–centered teaching approach and more sophisticated epistemological beliefs. These requirements of OBE poses a major challenge to teachers with more naive epistemological beliefs, because beliefs develop over years and are deeply rooted and difficult to change. With this study it was found that the participants’ epistemological beliefs could be typified as a system including more and less sophisticated epistemological beliefs, thus they did not only have naïve or sophisticated epistemological beliefs. It was also found that the participants of this study were more learner–centered than teacher–centered. Participants with more naïve epistemological beliefs were more teacher–centered compared to participants who had less naïve, thus more sophisticated epistemological beliefs that were more learner–centered. A relation was found between teachers with more naïve epistemological beliefs and a teacher–centered approach and teachers with less naïve epistemological beliefs (thus more sophisticated epistemological beliefs) and a learner–centered approach. / Thesis (M.Ed.)--North-West University, Potchefstroom Campus, 2011.

The research question addressed by this dissertation is: How is the tourist experience formed and what constitutes the authenticity of the tourist experience for two market segments (motivated and not motivated by learning) of tourists visiting (political) cultural heritage sites in South Africa. The study explores the correlation between three types of authenticity, namely objective, constructed and existential on two independent tourist samples, motivated and not motivated by learning. This research was initiated for three reasons. The first reason forms part of the research problem; South African cultural experiences received the lowest ratings from the international tourists despite the fact that culture and heritage play a role in reimaging South Africa from Big 5 destination into ‘It’s possible’ and ‘Leave ordinary behind’. It was suspected that not all types of cultural heritage products justify such a low ratings, especially not the political cultural heritage sites South Africa is famous for. The second reason emerged from the academic literature on authenticity theories and calls from the influential group of postmodernist scholars to declare the objective authenticity obsolete and replace it with the existential authenticity. The argument that; the hyperreal nature of the postmodern experience and its detachment from reality makes the authenticity of the site redundant, seemed inapt for cultural heritage sites exclusively dependent on their historical and authentic values. The third reason was the inability of the postmodern paradigm to explain the new tourism phenomenon driven by the tourists search for selfdevelopment through authentic experiences. The new emerging paradigm, transmodernity seemed to offer better theoretical framework in explaining the omnivorouessness of tourists’ consumption and the authentic nature of tourist experiences. The correlational character of the research question required a descriptive correlational design and quantitative methodology. The selected research instrument for primary data collection is a self–administered questionnaire. The sampling strategy is a non–probability sampling, and the sampling method is a convenience or accidental sample. The data was collected from November 2010 to February 2011 at the Constitutional Hill National Heritage Site in Johannesburg. The final sample (436) consists of 254 foreign and 182 domestic tourists. The questionnaire was designed to identify the variables pertinent to each type of authenticity of tourists experience and of the resultant tourist experience. The data analysis provided very interesting results. Firstly, the results of crosstabulation proved that more than half (56%) of the tourists expressed strong agreement that the Constitution Hill provided them with authentic experience, hence a proof that political heritage sites are not responsible for the overall low experiential ratings of the country’s culture and heritage. Secondly, the results of the Spearman’s correlation coefficient proved that objective authenticity as an independent variable have strong positive correlation with constructed and existential authenticity hence a proof that objective authenticity cannot be declared obsolete and replaced with existential authenticity. Finally, the results of the t–test proved that motivation for learning and place of birth do not play an important role in how tourist evaluate and experience the authenticity of the site pointing to the omnivorous nature of tourist consumption. In line with the transmodern paradigm, motivation for learning plays a critical role in triggering the transformative, authentic experience distinctive of the existential authenticity. The results of the study also showed that 32% of tourists are in fact the purposeful, New Age, transmodern Cultural Creatives. Proposed theoretical model of authenticity of tourists experience presents a theoretical platform for future research studies. / Thesis (M.A. (Tourism))--North-West University, Potchefstroom Campus, 2012.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized pathologically by a marked loss of dopaminergic nigrostriatal neurons and clinically by disabling movement disorders. PD can be treated by inhibiting monoamine oxidase (MAO), specifically MAO–B, since this is a major enzyme involved in the catabolism of dopamine in the substantia nigra of the brain. Inhibition of MAO–B may conserve the dopamine supply in the brain and may therefore provide symptomatic relief for PD patients. Selegiline is an irreversible MAO–B inhibitor and is currently used for the treatment of PD. Irreversible inhibitors inactivate enzymes by forming stable covalent complexes. The process is not readily reversed either by removing the remainder of the free inhibitor or by increasing the substrate concentration. Even dilution or dialysis does not dissociate the enzyme inhibitor complex and restore enzyme activity. From a safety point of view it may therefore be more desirable to develop reversible inhibitors of MAO–B. In this study, caffeine was used as lead compound to design, synthesize and evaluate new reversible inhibitors of MAO–B. This study is based on the finding that C–8 substituted caffeine analogues are potent MAO inhibitors. For example, (E)–8–(3–chlorostyryl)caffeine (CSC) is an exceptionally potent competitive inhibitor of MAO–B with an enzyme–inhibitor dissociation constant (Ki value) of 128 nM. In this study caffeine was similarly conjugated at C–8 to various side–chains. The effect that these chosen side–chains had on the MAO–B inhibition activity of C–8 substituted caffeine analogues will then be evaluated. The caffeine analogues were also evaluated as human MAO–A inhibitors. For the purpose of this study, saturated C–8 side chains were selected with the goal of discovering new C–8 side chains that enhance the MAO–A and ?B inhibition potency of caffeine. As mentioned above, the styryl side chain is one example of a side chain that enhances the MAO–B inhibition potency of caffeine. Should a side chain with promising MAO inhibition activity be identified in this study, the inhibition potency will be further optimized in a future study by the addition of a variety of substituents to the C–8 side chain ring. For example, halogen substitution of (E)–8– styrylcaffeine enhances the MAO–B inhibition potency by up to 10 fold. The saturated side chains selected for the present study included the phenylethyl (1), phenylpropyl (2), phenylbutyl (3) and phenylpentyl (4) functional groups. Also included are the cyclohexylethyl (8), 3–oxo–3– phenylpropyl (5), 4–oxo–4–phenylbutyl (6) moieties. A test compound containing an unsaturated linker between C–8 of caffeine and the side chain ring, the phenylpropenyl analogue 7, was also included. This study is therefore an exploratory study to discover new C–8 moieties that are favorable for MAO– inhibition. All the target compounds were synthesized by reacting 1,3–dimethyl–5,6–diaminouracil with an appropriate carboxylic acid in the presence of a carbodiimide dehydrating agent. Following ring closure and methylation at C–7, the target inhibitors were obtained. Inhibition potencies were determined using recombinant human MAO–A and MAO–B as enzyme sources. The inhibitor potencies were expressed as IC50 values. The most potent MAO–B inhibitor was 8–(5– phenylpentyl)caffeine (4) with an IC50 value of 0.656 ?M. In contrast, all the other test inhibitors were moderately potent MAO–B inhibitors. In fact the next best MAO–B inhibitor, 8–(4– phenylbutyl)caffeine (3) was approximately 5 fold less potent than 4 with an IC50 value of 3.25 ?M. Since the 5–phenylpentyl moiety is the longest side chain evaluated in this study, this finding demonstrates that longer C–8 side chains are more favorable for MAO–B inhibition. Interestingly, compound 5 containing a cyclohexylethyl side chain (IC50 = 6.59 ?M) was approximately 4 fold more potent than the analogue containing the phenylethyl linker (1) (IC50 = 26.0 ?M). This suggests that a cyclohexyl ring in the C–8 side chain of caffeine may be more optimal for MAO–B inhibition and should be considered in future studies. The caffeine analogues containing the oxophenylalkyl side chains (5 and 6) were weak MAO–B inhibitors with IC50 values of 187 ?M and 46.9 ?M, respectively. This suggests that the presence of a carbonyl group in the C–8 side chain is not favorable for the MAO–B inhibition potency of caffeine. The unsaturated phenylpropenyl analogue 7 was also found to be a relatively weak MAO–B inhibitor with an IC50 value of 33.1 ?M. In contrast to the results obtained with MAO–B, the test caffeine analogues were all weak MAOA inhibitors. With the exception of compound 5, all of the analogues evaluated were selective inhibitors of MAO–B. The most potent MAO–B inhibitor, 8–(5–phenylpentyl)caffeine (4) was the most selective inhibitor, 48 fold more potent towards MAO–B than MAO–A. This study also shows that two selected analogues (5 and 3) bind reversibly to MAO–A and ?B, respectively, and that the mode of MAO–A and –B inhibition is competitive for these representative compounds. / Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2011.