Browsing by Author "Joubert, J."
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Item Design and synthesis of polycyclic amine derivatives for sigma receptor activity(2013) Strydom, Natasha; Malan, S.F.; Joubert, J.New therapeutic strategies are needed for a diverse array of poorly understood neurological impairments. These include neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease, and the psychiatric disorders such as depression, anxiety and drug dependence. Popular neuropharmacotherapies have focused on dopamine (DA), serotonin (5HT), γ-aminobutric acid (GABA) and glutamate systems (Jupp & Lawrence, 2010). However recent research points to the sigma receptor (σR) as a possible neuromodulatory system. Due to its multi-receptor action, the σR can trigger several significant biological pathways. This indicates its ideal potential as a drug target to effectively minimise drug dosage and potential side effects. Currently there are a limited number of σR ligands available and few possess the selectivity to significantly show σR’s role in neurological processes. Polycyclic amines have shown notable sigma activity and provide an advantageous scaffold for drug design that can improve pharmacodynamic and pharmacokinetic properties (Banister et al., 2010; Geldenhuys et al., 2005). Aryl-heterocycle amine groups were also shown to improve σR activity (Piergentili et al., 2009).Item Design, Synthesis and Evaluation of Indole Derivatives as Multifunctional Agents against Alzheimer's disease.(University of the Western Cape, 2017) Denya, Ireen; Joubert, J.; Malan, S. F.Alzheimer's disease (AD) is an age related neurodegenerative disorder characterised by progressive memory loss and cognitive impairment. It is one of several neurodegenerative disorders occurring as a result of a process of programmed cell death known as apoptosis. The process is set off by various stimuli in numerous pathways that ultimately lead to apoptosis. AD stands out as one of the leading causes of death in the elderly in today's society. The cholinergic hypothesis of AD states that there is an extensive loss of cholinergic neurons in the central nervous system that contributes to cognitive impairment. Acetylcholinesterase inhibitors decrease the breakdown of the neurotransmitter acetylcholine to maintain its post synaptic levels and compensate for the loss of functional brain cells. Amyloid ? plaque formation has been shown to be extensively involved in the pathogenesis of AD. The abnormal regulation of the amyloid precursor protein gives rise to plaques that impair neuronal homeostasis and eventually lead to apoptosis. The monoamine oxidase enzymes catalyse the hydrolysis of amine neurotransmitters such as dopamine. The process produces peroxides that cause oxidative stress alongside the depletion of neurotransmitters. Inhibition of monoamine oxidase allows for accumulation of neurotransmitters and reduces the formation of oxidative free radicals to confer neuroprotection.Item Hybrid molecules as inhibitors of the monoamine oxidases and caspase 3 for neurodegenerative disorders(University of the Western Cape, 2016) Tavari, Mohsen; Joubert, J.; Malan, S.FNeurodegenerative diseases are multifactorial in nature, and taking the complex nature of these disorders into consideration, multi-target directed ligands may present as better options to treat these disorders than the classic ‘one molecule, one target’ approach. Neurotransmitter amines are catabolized by monoamine oxidase A and B (MAO-A and MAO-B), therefore they have been targeted for the treatment of neuropsychiatric and neurodegenerative diseases. Besides offering a potential antidepressant action in PD, MAO-A inhibitors may also provide a symptomatic benefit by reducing MAO-A-catalysed oxidation of dopamine. The oxidative deamination reaction catalyzed by MAO-B is one of the major catabolic pathways of dopamine in the brain. Inhibition of this enzyme leads to enhanced dopaminergic neurotransmission and are currently used in the symptomatic treatment of PD. Furthermore, MAO-B inhibitors may also exert neuroprotective effects by reducing the concentration of potentially hazardous by-products produced by MAO-B-catalysed dopamine oxidation. Apoptosis or programmed cell death occurs in a number of neurodegenerative disorders and it has been proven that inhibition of the executing enzyme, caspases-3, slows down or even stops apoptosis. Having this in mind we focused on the propargylamine function of selegiline and the fluorophenyl function of safinamide, because of their inherent monoamine oxidase inhibitory activities; and isatin as a non-peptide inhibitor of caspase-3. Therefore we attempted to design and synthesize multifunctional hybrid molecules acting simultaneously to halt the apoptotic neuronal breakdown process and eliminate the signs and symptoms of diseases such as PD. Seven novel compounds were successfully synthesized utilizing multistep processes. The synthesis of 5 chlorosulfonyl isatin was accomplished starting from the commercially available isatin in two steps, which were, sulfonation using tetramethylene sulfone and chlorination with POCl₃. Next 5-chlorosulfonyl isatin was conjugated to the fluorophenylamine derivative with the fluoro-function at either the ortho, meta or para position through a nucleophilic substitution reaction on the chlorosulfonyl position. The resultant compounds were coupled on the N position of the isatin function with propargyl bromide, using a microwave synthesis procedure, in a nucleophilic substitution reaction. The structures and purity were confirmed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). In the biological evaluations recombinant human MAO-A, MAO-B and caspase 3 enzymatic assays were performed to determine the activity of the novel compounds at an enzymatic level. The inhibition percentages for these compounds were calculated and plotted against the logarithm 8 of the inhibitor concentrations to obtain a sigmoidal dose-response curve and consequently the IC50 value. The synthesized compounds showed inhibition of the MAO-A, MAO-B and caspase-3 enzymes at low to high micro molar concentrations. The role of the fluorophenylamine moiety in the synthesized compounds was significant for their multifunctional activity as shown by compounds 3 and 4 having good inhibitory activity towards MAO-A, MAO-B and also excellent inhibitory activity against caspase 3, making those ideal candidates for further lead compound development and multifunctional drug design. The introduction of the propargylamine moiety only increased the MAO-A inhibitory activity; this was shown by compounds 7, 8 and 9 which exhibit good MAO-A selectivity with low MAO-B and caspase-3 inhibitory activities.Item Novel adamantane derivatives as multifunctional neuroprotective agents(University of the Western Cape, 2013) Kadernani, Yakub Esmail Y.E.; Joubert, J.The pathology of neurodegenerative disorders involves multiple steps, and it is probably for this reason that targeting one particular step in a multi-step process has only yielded limited results. Nitric oxide (NO) is synthesised from L-Arginine by an enzyme known as nitric oxide synthase (NOS). Three isoforms of NOS exist, including endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). In the central nervous system (CNS), nNOS is involved in the synthesis of NO, which is involved in various neurological functions. NO is a free radical and this probably explains why an excess amount of it has been implicated in the development of neurodegenerative disorders. In the CNS, the Nmethyl- D-aspartate (NMDA) receptor in its active state allows the influx of calcium ions which activate nNOS thus increasing the amount of NO and other detrimental reactive nitrogen species within neuronal cells. Calcium entry through voltage-gated calcium channels (VGCC) may also contribute to this. Although calcium ions are important for physiological functioning, an excess is responsible for excitotoxicity, which can ultimately lead to neurodegeneration. Our aim was to synthesise a series of adamantane-derived compounds that act at multiple target sites in the neurodegenerative pathway. By conjugating benzyl and phenylethyl moieties with different functional groups (-H, -NO2, -NH2, -NHC(NH)NH2, -OCH3) to the amantadine structure, we aimed to synthesise compounds that display calcium channel and NMDA receptor (NMDAR) channel inhibition, as well as selective inhibition of nNOS. A series of compounds (-H, -NO2, -NH2, -OCH3) were obtained in yields that varied between 16.5 % and 90.25 %. These novel compounds were tested for calcium influx through VGCC and NMDAR inhibition using synaptoneurosomes isolated from rat brain homogenate against the reference compounds MK-801, NGP1-01, amantadine, memantine and nimodipine. A lack of success with the synthesis of the guanidine compounds prevented the use of the oxyhemoglobin capture assay for the determination of nNOS inhibitory activity of these compounds. The novel synthesised compounds display inhibitory activity towards VGCC and the NMDAR in the micromolar range. Further tests are recommended on compounds SE-1, SE-4, SE-11 and SE-12 as they displayed good inhibitory activity against both NMDAR- as well as ii KCl-mediated calcium influx. These novel compounds may be better therapeutic options than amantadine and memantine as they inhibit both NMDAR and VGCC-mediated calcium influx, whereas amantadine and memantine only inhibit NMDA-mediated calcium influx. These novel adamantane derived compounds may possibly serve as novel leads or potential therapeutic agents for the treatment of neurodegenerative disorders.Item Novel aminoquinoline-polycyclic hybrid molecules as potential antimalarial agents(University of the Western Cape, 2014) Fortuin, Elton E.; Malan, S. F.; Joubert, J.Plasmodium falciparum malaria continues to be a worldwide health problem, especially in developing countries in Africa and is responsible for over a million fatalities per annum. Chloroquine (CQ) is low-cost, safe and was the mainstay aminoquinoline derived chemotherapeutic agent that has been used for many years against blood-stage malaria. However, today the control of malaria has been complicated by increased resistance of the malaria parasite to existing antimalarial agents such as CQ. The primary cause of resistance is mutation in a putative ATP-powered multidrug efflux pump known as the p-glycoprotein (pGP) pump, and point mutation in P. falciparum CQ resistance transporter (PfCRT) protein. These mutations are responsible for the reduced accumulation of CQ at its primary site of action, the acidic digestive food vacuole of the parasite.To overcome the challenges of CQ resistance in P. falciparum, chemosensitiser offer an attractive approach. Chemosensitisers or reversal agents are structurally diverse molecules that are known to reverse CQ resistance by inhibiting the pGP efflux pump and/or the PfCRT protein associated with CQ export from the digestive vacuole in CQ resistant parasites. Chemosensitisers include the well-studied calcium channel blocker verapamil and antihistaminic agent chlorpheniramine. These drugs have little or no inherent antimalarial activity but have shown to reverse CQ resistance in P. falciparum when co-administered with CQ. Because of the channel blocking abilities of pentacycloundecylamines (PCUs) such as NGP1-01, it is postulated that these agents may act as chemosensitisers and circumvent the resistance of the Plasmodium parasite against CQ. Therefore as a proof of concept we conducted an experiment using CQ co- administered with different concentrations of NGP1-01 to evaluate the ability of NGP1-01 to act as a chemosensitiser.Herein, we report the ability of NGP1-01, the prototype pentacycloundecylamine (PCU), to reverse CQ resistance (> 50 %) and act as a chemosensitiser. NGP1-01 alone exhibited very low intrinsic antimalarial activity against both the resistant and sensitive strain (> 2000 nM), with no toxicity to the parasite detected at 10 µM. A statistically significant (p < 0.05) dose dependent shift was seen in the CQ IC50 values at both 1 µM and 10 µM concentration of co-administeredNGP1-01 against the resistant strain. Based on this finding we set out to synthesise a series of novel agents comprising of a PCU moiety as the reversal agent (RA) conjugated to a CQ-like aminoquinoline (AM) molecule and evaluate the potential of these PCU-AM derivatives as antimalarial- and/or reversed CQ agents. As recently shown by Peyton et al., (2012), the conjugation of a CQ-like molecule with a RA such as the chemosensitiser imipramine and derivatives thereof is a viable strategy to reverse CQ resistance in multidrug-resistant P. falciparum. The novel compounds were obtained by amination and reductive amination reactions. The synthetic procedures involved the conjugation of the Cookson’s diketone with different tethered 4-aminoquinoline moieties to yield the respective carbinolamines and the subsequent imines. This was followed by a transannular cyclisation using sodium cyanoborohydride as reducing agent to yield the desired PCU-AM derivatives. The CQ-like AMderivatives were obtained using a novel microwave (MW) irradiation method. Structure elucidation was done by utilising 1H- and 13C NMR spectroscopy as well as IR absorption spectrophotometry and mass spectrometry. Five PCU-AM reversed CQ derivatives were successfully synthesised and showed significant in vitro antimalarial activity against the CQ sensitive strain (NF54). PCU-AM derivatives 1.1 – 1.4 showed antimalarial IC50 values in the ranges of 3.74 – 17.6 ng/mL and 27.6 – 253.5 ng/mL against the CQ-sensitive (NF54) and CQ-resistant strains (Dd2) of Plasmodium falciparum, respectively. Compound 1.1 presented with the highest antimalarial activity against both strains and was found to be 5 fold more active against the resistant strain than CQ. The reversed CQ approach resulted in improved resistance reversal and a significantly lower concentration PCU was required compared to NGP1-01 and CQ in combination. This may be attributed to the improved ability of compound 1.1 to actively block the pGP pump and/or the increased permeability thereof because of the lipophilic aza-PCU moiety. Compound 1.1 also showed the lowest RMI value confirming that this compound has the best potential to act as a reversed CQ agent in the series. Cytotoxicity IC50 values observed for compounds 1.1 – 1.4 were in the low micromolar concentrations (2.39 – 9.54 µM) indicating selectivity towards P. falciparum (SI = 149 – 2549) and low toxicity compared to the cytotoxic agent emetine (IC50 = 0.061 µM).These results indicate that PCU channel blockers and PCU-AM derived conjugates can be utilised as lead molecules for further optimisation and development to enhance their therapeuticpotential as reversal agents and reversed CQ compounds.Item Synthesis and evaluation of novel coumarin-donepezil derivatives as dual acting monoamine oxidase B and cholinesterase in Alzheimer's disease(University of the Western Cape, 2016) Foka, Germaine Boulenoue; Joubert, J.; Malan, S. F.; Kapp, E.Alzheimer's disease is a progressive neurodegenerative disease characterised by low acetylcholine (ACh) levels in the hippocampus and cortex of the brain, causing symptoms like progressive memory loss, decline in language skills and other cognitive impairments to occur. The hallmarks of AD include the presence of extracellular insoluble amyloid beta plaques, intracellular neurofibrillary tangles, and the decrease in ACh concentration. The pathophysiology of AD is not well understood, however, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and monoamine oxidases (MAO) are conspicuous role players in AD pathogenesis. Based on the cholinergic hypothesis, the AChE inhibitor donepezil was developed and has been used effectively clinically in the management of AD, with minimal side effects. Studies regarding the binding interactions of donepezil with AChE has shown that the benzyl-piperidine moiety of this compound shows substantial binding interactions at the CAS site of AChE where it blocks AChE activity. Coumarin is a compound of natural source that has shown some MAO inhibitory activity. Further studies done to clarify the potential of coumarin as a drug against AD has shown that coumarin has the capacity to bind at the PAS site of AChE, thus giving it the potential to prevent AChE induced amyloid plaque formation. Due to the multifactorial nature of AD, the drugs in the market show limited therapeutic benefits and are mainly for symptomatic relief. In order to address this limitation in AD treatment, researchers are exploring the possibility of designing a multi-target-directed-ligand (MTDL). The aim of this study was to synthesise a series of compounds out of pharmacophoric groups of donepezil and coumarin that will be able to inhibit both cholinesterases and MAO B. Four series of 5 compounds per series were synthesised. The first series of compounds consisted of the coumarin moiety to which a 1,4-dibromo benzene moiety was attached. The second series represented the coumarin moiety to which a piperidine (donepezil moiety shown to confer cholinesterase inhibitory property) was attached. The third series represented the coumarin moiety to which bromobenzyl-piperazine was attached and in the last series were compounds similar in structure to series 1 with an unsubstituted benzyl moiety as opposed to the dibromobenzyl moiety. Prior to the synthesis, molecular modelling was conducted in order to have an idea of the binding capacity of the compounds to MAO A and B and cholinesterases. In vitro biological evaluation of the compounds was done and used to determine the IC₅₀ values of the compounds. Nineteen compounds were synthesised and purified successfully as shown by their NMR, MS and IR spectra. The compounds to which dual inhibitory activity was conferred were those in series 2 and 3, of which series 2 showed the best overall inhibitory activity with IC₅₀ values within the low μM range. The compound with the best overall activity was Cp 9. Molecular modelling of Cp 9 showed that the coumarin core was located in the PAS region of AChE while the benzyl-piperidine moiety was situated in the CAS region of the enzyme. This compound orientation demonstrates the potential of Cp 9 to inhibit AChE induced amyloid beta plaque formation. Cp 9 showed no inhibitory activity towards MAO A, but showed good inhibitory activity towards MAO B with an IC₅₀ value of 0.30 μM. Its inhibitory activity towards cholinesterases also fell within the low μM range (AChE IC50 = 9.1 μM and BuChE IC₅₀ = 5.9 μM). From the results, it can be concluded that Cp 9 was able to inhibit both cholinesterase and MAO B catalytic activities at low μM concentrations. This thus means that our novel compound will not only increase ACh levels in the brain thus improving cognitive activity, but it will also have neuroprotective effect from its MAO B inhibitory property and also potentially slow down amyloid plaque formation due to AChE activity.Item Synthesis of 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives as lead scaffolds for neuroprotective agents(ARKAT USA, 2020) Egunlusi, A.O.; Malan, S.F.; Joubert, J.Neurodegenerative disorders are characterised by progressive loss of neuronal functions. Of the proposed mechanisms, excitotoxicity, mediated by prolonged glutamate activation and calcium overload, is prominent. NGP1-01, a polycyclic cage amine, and tricyclo[6.2.1.02,7]undec-9-ene-3,6-dione have been shown to display calcium-modulating properties. In this study, we synthesised structurally-related 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione as the base scaffold, and incorporated various functional moieties through aminolysis, to afford a series of imide derivatives. All final compounds were obtained in yields between 47-97% and their structures were confirmed by NMR, IR and MS. These structurally-related derivatives could potentially act as neuroprotective agents. Additionally, their synthetic versatilities could make them precursors, as lead compounds, to potential pharmacologically-active agents.