UWCScholar :: Browsing by Author "Malan, Sarel"

Browsing by Author "Malan, Sarel"

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Chalcone and curcumin hybrids of indole propargylamines as multifunctional neuroprotective agents
(University of the Western Cape, 2020) Musakwa, Lovetone; Joubert, Jacques; Malan, Sarel
Neurodegenerative disorders (NDs) are a range of chronic brain disorders that includes amongst others motor function loss. Parkinson’s disease (PD) is one of the common NDs that has an insidious onset and diagnosed when dopaminergic neurons in the substantia nigra are already lost. The loss creates a deficiency of the dopamine (neurotransmitter) thereby causing neurochemical imbalance resulting in the signs and symptoms of PD. NDs overlap at multiple levels so some of the symptoms overlap as well. NDs currently have no cure yet and current drug therapies only improve the quality of life of the patients by targeting the symptoms mainly. Treatment of PD currently involves different classes of drugs and depending on the stages of the disease, some drugs can be only used as an adjunct therapy. Anti-oxidants and monoamine oxidase inhibitors (MAO-I) are part of the treatment options.
Computational strategies to identify, prioritize and design potential antimalarial agents from natural products
(University of the Western Cape, 2015) Egieyeh, Samuel Ayodele; Christoffels, Alan; Malan, Sarel; Syce, James
Introduction: There is an exigent need to develop novel antimalarial drugs in view of the mounting disease burden and emergent resistance to the presently used drugs against the malarial parasites. A large amount of natural products, especially those used in ethnomedicine for malaria, have shown varying in-vitro antiplasmodial activities. Facilitating antimalarial drug development from this wealth of natural products is an imperative and laudable mission to pursue. However, the limited resources, high cost, low prospect and the high cost of failure during preclinical and clinical studies might militate against pursue of this mission. Chemoinformatics techniques can simulate and predict essential molecular properties required to characterize compounds thus eliminating the cost of equipment and reagents to conduct essential preclinical studies, especially on compounds that may fail during drug development. Therefore, applying chemoinformatics techniques on natural products with in-vitro antiplasmodial activities may facilitate identification and prioritization of these natural products with potential for novel mechanism of action, desirable pharmacokinetics and high likelihood for development into antimalarial drugs. In addition, unique structural features mined from these natural products may be templates to design new potential antimalarial compounds. Method: Four chemoinformatics techniques were applied on a collection of selected natural products with in-vitro antiplasmodial activity (NAA) and currently registered antimalarial drugs (CRAD): molecular property profiling, molecular scaffold analysis, machine learning and design of a virtual compound library. Molecular property profiling included computation of key molecular descriptors, physicochemical properties, molecular similarity analysis, estimation of drug-likeness, in-silico pharmacokinetic profiling and exploration of structure-activity landscape. Analysis of variance was used to assess statistical significant differences in these parameters between NAA and CRAD. Next, molecular scaffold exploration and diversity analyses were performed on three datasets (NAA, CRAD and malarial data from Medicines for Malarial Ventures (MMV)) using scaffold counts and cumulative scaffold frequency plots. Scaffolds from the NAA were compared to those from CRAD and MMV. A Scaffold Tree was also generated for all the datasets. Thirdly, machine learning approaches were used to build four regression and four classifier models from bioactivity data of NAA using molecular descriptors and molecular fingerprints. Models were built and refined by leave-one-out cross-validation and evaluated with an independent test dataset. Applicability domain (AD), which defines the limit of reliable predictability by the models, was estimated from the training dataset and validated with the test dataset. Possible chemical features associated with reported antimalarial activities of the compounds were also extracted. Lastly, virtual compound libraries were generated with the unique molecular scaffolds identified from the NAA. The virtual compounds generated were characterized by evaluating selected molecular descriptors, toxicity profile, structural diversity from CRAD and prediction of antiplasmodial activity. Results: From the molecular property profiling, a total of 1040 natural products were selected and a total of 13 molecular descriptors were analyzed. Significant differences were observed between the natural products with in-vitro antiplasmodial activities (NAA) and currently registered antimalarial drugs (CRAD) for at least 11 of the molecular descriptors. Molecular similarity and chemical space analysis identified NAA that were structurally diverse from CRAD. Over 50% of NAA with desirable drug-like properties were identified. However, nearly 70% of NAA were identified as potentially "promiscuous" compounds. Structure-activity landscape analysis highlighted compound pairs that formed "activity cliffs". In all, prioritization strategies for the natural products with in-vitro antiplasmodial activities were proposed. The scaffold exploration and analysis results revealed that CRAD exhibited greater scaffold diversity, followed by NAA and MMV respectively. Unique scaffolds that were not contained in any other compounds in the CRAD datasets were identified in NAA. The Scaffold Tree showed the preponderance of ring systems in NAA and identified virtual scaffolds, which maybe potential bioactive compounds or elucidate the NAA possible synthetic routes. From the machine learning study, the regression and classifier models that were most suitable for NAA were identified as model tree M5P (correlation coefficient = 0.84) and Sequential Minimization Optimization (accuracy = 73.46%) respectively. The test dataset fitted into the applicability domain (AD) defined by the training dataset. The “amine” group was observed to be essential for antimalarial activity in both NAA and MMV dataset but hydroxyl and carbonyl groups may also be relevant in the NAA dataset. The results of the characterization of the virtual compound library showed significant difference (p value < 0.05) between the virtual compound library and currently registered antimalarial drugs in some molecular descriptors (molecular weight, log partition coefficient, hydrogen bond donors and acceptors, polar surface area, shape index, chiral centres, and synthetic feasibility). Tumorigenic and mutagenic substructures were not observed in a large proportion (> 90%) of the virtual compound library. The virtual compound libraries showed sufficient diversity in structures and majority were structurally diverse from currently registered antimalarial drugs. Finally, up to 70% of the virtual compounds were predicted as active antiplasmodial agents. Conclusions:Molecular property profiling of natural products with in-vitro antiplasmodial activities (NAA) and currently registered antimalarial drugs (CRAD) produced a wealth of information that may guide decisions and facilitate antimalarial drug development from natural products and led to a prioritized list of natural products with in-vitro antiplasmodial activities. Molecular scaffold analysis identified unique scaffolds and virtual scaffolds from NAA that possess desirable drug-like properties, which make them ideal starting points for molecular antimalarial drug design. The machine learning study built, evaluated and identified amply accurate regression and classifier accurate models that were used for virtual screening of natural compound libraries to mine possible antimalarial compounds without the expense of bioactivity assays. Finally, a good amount of the virtual compounds generated were structurally diverse from currently registered antimalarial drugs and potentially active antiplasmodial agents. Filtering and optimization may lead to a collection of virtual compounds with unique chemotypes that may be synthesized and added to screening deck against Plasmodium.
Evaluation of selected polycyclic compounds as resistance modulators in Mycobacterium tuberculosis
(University of the Western Cape, 2022) Kapp, Erika; Malan, Sarel
Progressive development of resistance to various chemotherapeutic agents used in the management of infectious diseases presents a serious problem in global public health. Increasing levels of antimicrobial resistance in Mycobacterium tuberculosis (Mtb) is particularly concerning in resource poor countries with a high incidence of tuberculosis (TB), as it is particularly difficult and very costly to treat. The Global Tuberculosis report released by the World health Organization (WHO) in 2022 (based on data from 2021) reports that South Africa is one of only 5 countries in the world with more than 500 cases per 100 000 people. It also falls in the WHO’s top 7 countries with the highest multidrug resistant (MDR) TB incidence.1 The same report released in 2021 states that global TB reporting rates dropped dramatically in 2020, and that TB death rates saw the first year-on-year increase since 2005.2 This is likely a direct consequence of COVID-19 and although improvements in reporting was seen in 2021, the trend has not yet been reversed.1 The pandemic had a negative impact on the progress made in the fight against TB and a renewed effort is needed to achieve the goals previously set out in the WHO End TB Strategy.
Novel adamantane-chloroquinolin conjugates to overcome plasmodium falciparum chloroquine resistance
(University of the Western Cape, 2017) Yvette, Mofenge Opute; Joubert, Jacques; Malan, Sarel
Malaria poses devastating health and socioeconomic outcomes on global health especially among pregnant women and children below the age of 5 in endemic areas. This is exacerbated by Plasmodium falciparum resistance to available antimalarial drugs, especially chloroquine (CQ), which was the drug of choice for many years against the blood stage of malaria.
Novel norbornane derivatives as potential neuroprotective agents
(University of Western Cape, 2020) Egunlusi, Ayodeji Olatunde; Joubert, Jacques; Malan, Sarel
Neurodegenerative disorders are characterised by progressive loss of the brain’s physiological functions as a result of gradual degeneration of neurons in the central nervous system. Even though they are classified as diseases of the elderly, occurrence earlier in life is possible, but that would suggest the influence of genetic and/or environmental factors. Due to the continuous rise in modernisation and industrialisation over the years, there has been an increase in incidence and prevalence of neurodegenerative disorders. With the advances in technology and life expectancy, the rates of the common forms (Alzheimer’s disease and Parkinson’s disease), are expected to increase exponentially by 2050. Unfortunately, there is still no clinically approved treatment or therapy to slow down or halt the degenerative process as most registered drugs only offer symptomatic relief. Confounding this issue is the lack of definite mechanism of neurodegeneration, which is still poorly defined and not completely understood. Nonetheless, the pathology of most neurodegenerative disorders is believed to be a combination of interrelated processes that eventually leads to neuronal cell death. Among the postulated processes, the impact of excitotoxicity mediated by NMDA receptor over-activation is prominent and it is implicated in virtually all neurodegenerative disorders. With this basic insight, it is believed that molecules capable of inhibiting NMDA receptors and associated calcium channels, without affecting the normal physiological functions of the brain, could potentially serve as good neuroprotective drugs. Competitive and uncompetitive blockers (MK-801 and ketamine) have been explored, but none were clinically accepted due to undesirable side effects such as hallucinations, sedation and depression. However, NGP1-01, a polycyclic cage molecule, has been shown to be neuroprotective through modulation of NMDA receptors and voltage gated calcium channels and attenuation of MPP+ -induced toxicity. A similar approach could be useful in the design and development of new neuroprotective drugs. The aim of this study was to synthesise a series of open and rearranged cage-like molecules and explore their neuroprotective potential in neuroblastoma SH-SY5Y cells. The proposed structures, with norbornane scaffolds that contained different moieties, were designed to structurally resemble NGP1-01 and MK-801. Once synthesised, the compounds were purified and characterised, and were evaluated for their biological activities. Compounds were first screened for cytotoxicity at different concentrations. Thereafter, they were evaluated for neuroprotective effects against MPP+ -induced excitotoxicity and for calcium flux modulatory effects on NMDA receptor and voltage gated calcium channels. The norbornane derivatives were synthesised and characterised, and all final products were afforded in sufficient yields. All compounds with the exception of two compounds displayed good cytotoxic profiles towards the SH-SY5Y neuroblastoma cells at 10 µM, 50 µM and 100 µM concentrations as they demonstrated percentage cell viabilities close to 100% (control treated cells). Only two compounds showed percentage cell viability of 51% and 59% at 100 µM. Utilising the same cell line, all compounds, tested at 10 µM, attenuated MPP+ -induced toxicity after 24 hours of exposure to a neurotoxin. This was evident in the 23% to 53% enhancement (significant with p < 0.05) in cell viability when compared to the MPP+ only treated cells. In comparison to known NMDA receptor and/or voltage gated calcium channel blockers (MK-801, NGP1-01 or nimodipine), the synthesised compounds demonstrated mono or dual inhibition of calcium channels as they effectively attenuated calcium influx by blocking NMDA receptors and/or voltage gated calcium channels expressed in neuroblastoma SHSY5Y cells. This group of compounds were found to be more potent NMDA receptor inhibitors, probably due to similarities with MK-801 and memantine, than voltage gated calcium channel inhibitors. All compounds demonstrated moderate to good calcium inhibitory effects at NMDA receptors in the range of 23% to 70% while a selected few displayed very little or no activity at the voltage gated calcium channels. In conclusion, 27 compounds with norbornane scaffolds were successfully synthesised and evaluated for cytotoxicity and neuroprotection. The abilities of the synthesised compounds to protect neurons from the neurotoxin MPP+ and reduce calcium flux into neuronal cells were successfully demonstrated. These characteristics are essential in neuroprotection as they may prove significant in halting or slowing down the disease progression. The compounds showing a good cytotoxicity profile, neuroprotective effects and ability to reduce calcium overload, could potentially act as neuroprotective agents with good safety profiles or contribute as lead structures to the development and design of structurally related molecules that could clinically benefit people with neurodegenerative disorders.
Novel tricycloundecane derivatives as potential N-methyl-Daspartate receptor and calcium channel inhibitors for neuroprotection
(University of the Western Cape, 2014) Egunlusi, Ayodeji Olatunde; Joubert, Jacques; Malan, Sarel
This study focused on the synthesis of a series of novel tricycloundecane derivatives and evaluation of these compounds for neuroprotection using the fluorescent ratiometric calcium assay that indicates the ability of the test compounds to inhibit NMDA receptors and VGCC. The cycloaddition reaction between p-benzoquinone and monomerised dicyclopentadiene yielded tricycloundeca- 4,9-diene-3,6-dione which was used as the base structure and further derivatised. These derivatives were conjugated with benzylamine to form a series of imines and amines. A total of 10 compounds were synthesised for evaluation of inhibition of calcium influx through NMDA receptor channels and voltage-gated calcium channels. The structures were confirmed using NMR, IR and MS. On the proton NMR, the characteristic AB-quartet system was observed in the region of 1-2 ppm for all the compounds and the aromatic moiety was observed between 6.5-7.5 ppm for the novel polycyclic amines. These, with other functional groups, were used to confirm the individual structures
Selection, synthesis and evaluation of novel drug-like compounds from a library of virtual compounds designed from natural products with antiplasmodial activities
(University of the Western Cape, 2020) Pokomi, Rostand Fankam; Joubert, Jacques; Malan, Sarel; Egieyeh, Samuel
Malaria is an infectious disease which continues to kill more than one million people every year and the African continent accounts for most of the malaria death worldwide. New classes of medicine to combat malaria are urgently needed due to the surge in resistance of the Plasmodium falciparum (the parasite that causes malaria in humans) to existing antimalarial drugs. One approach to circumvent the problem of P. falciparum resistance to antimalarial drugs could be the discovery of novel compounds with unique scaffolds and possibly new mechanisms of action. Natural products (NP) provide a wide diversity of compounds with unique scaffolds, as such, a library of virtual compounds (VC) designed from natural products with antiplasmodial activities (NAA) can be a worthy starting point.
Synthesis and evaluation of 7-substituted 3-propargylamine coumarin derivatives as multifunctional monoamine oxidase and cholinesterase inhibitors for Alzheimer’s Disease treatme
(University of Western Cape, 2020) Mzezewa, Sheunopa C.; Joubert, Jacques; Malan, Sarel
Alzheimer’s Disease (AD) is a neurodegenerative disease which results from the irreversible loss of neurons in the brain. The disease is characterized by progressive cognitive impairment with recurrent short-term memory loss. AD is the leading cause of dementia and 4th leading cause of death in the elderly. Success in the treatment of AD has been limited, with drugs only treating it at a symptomatic level due to its pathology being complex and poorly understood. However, it is known that the cholinesterase and MAO-B enzymes play an important role in the disease through their association with production of amyloid plaques and oxidative stress respectively, two mechanisms associated with cell death and the symptoms seen in AD.
Transparency in medicines registration decision making: A closer look at National Medicines Regulatory Authorities (NMRAs) within the Southern African Development Community (SADC) region.
(University of the Western Cape, 2020) Ratlabyana, Mphako Brighton; Malan, Sarel
Medicines registration decision-making and regulatory best practice involve transparent and consistent rule making and processes with publicly available published assessment decisions and reports (Kaine, 2020). Publication of information relating to evaluation of medicines in the form of Public Assessment Reports (PARs) is one way of ensuring transparency in medicines registration decision making. It is however not clear whether National Medicines Regulatory Authorities (NMRAs) in the Southern African Development Community (SADC) region are in a position to generate or even publish such PARs / summary basis for registration of medicines. Objectives: The study investigated transparency in medicines registration decision-making processes for NMRAs within the SADC region. Specifically, the availability or non-availability of PARs / Summary basis for registration of medicinal products. To establish if all SADC NMRAs have legislative frameworks for regulating medicines and to investigate the sources of funding for SADC NMRAs. Methods: A cross-sectional exploratory descriptive study design with qualitative techniques by questionnaire as a data collection tool was used. Questionnaires were sent via email to senior members / key informants of 11 regulatory authorities belonging to SADC. Trend analysis was conducted based on the emerging themes from questionnaire response. Results The study revealed that currently five (5) NMRAs are operating as semi-autonomous agencies namely: BOMRA, MCAZ, PMRA, SAHPRA and TMDA .While NMRC, DNME of Angola, ACOREP of DRC and DNF of Mozambique are functioning within their respective Ministries of Health Departments. Furthermore, all NMRAs have a legislation framework governing the regulation of medicines in their respective jurisdictions. However, DNME of Angola’s legal framework is not yet officially formalised and as such, they follow a Presidential decree enacted in 2010. Four (4) of nine (9) NMRAs (44 %) reported to have more than 20 internal assessors / evaluators. This indicates a significant milestone for SADC NMRAs in terms of capacity building within the region. The study findings indicated that the SADC NMRAs are receiving funding from multiple sources ranging from a minimum of one to maximum of four funding sources. There were only two NMRAs, MCAZ and PMRA, that were not receiving funding from their governments. The study results further indicates that only TMDA is able to generate and publish PARs amongst SADC NMRAs. Conclusions: The findings in this study suggest that the majority of NMRAs within SADC are not yet matured as compared to countries in the developed world such as the US, Europe, Canada and Australia. It can also be concluded that for SADC NMRAs to be efficient and responsive, they will require massive financial resources. For example, the budget for a matured NMRA such as the US Food and Drug Administration (US FDA) for the 2019 financial year was estimated at US$ 5.7 billion. Literature further indicates that publication of the summary basis of approval or PARs is a norm for mature NMRAs and acts as a tool for regulatory authorities to build and establish confidence in their review processes and provides assurance regarding safety of medicines. The study results indicate that TMDA is publishing PARs or summary of grounds on which approvals are granted. This demonstrates a significant level of transparency in the TMDA medicines registration processes and therefore other SADC NMRAs can benchmark with TMDA to implement this key parameter.

Browsing by Author "Malan, Sarel"

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