Browsing by Author "Kapp, Erika"

Now showing 1 - 6 of 6
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    Antimycobacterial Activity, Synergism, and Mechanism of Action Evaluation of Novel Polycyclic Amines against Mycobacterium tuberculosis
    (Advances in Pharmacological and Pharmaceutical Sciences, 2021-06) Kapp, Erika; Joubert, Jacques; Sampson, Samantha, L; Malan, Sarel, F; Sharma, Rajan; Warner, Digby, F; Seldon, Ronnett; Jordaan, Audrey; de Vos, Margaretha
    Mycobacterium tuberculosis has developed extensive resistance to numerous antimycobacterial agents used in the treatment of tuberculosis. Insufficient intracellular accumulation of active moieties allows for selective survival of mycobacteria with drug resistance mutations and accordingly promotes the development of microbial drug resistance. Discovery of compounds with new mechanisms of action and physicochemical properties that promote intracellular accumulation, or compounds that act synergistically with other antimycobacterial drugs, has the potential to reduce and prevent further drug resistance. To this end, antimycobacterial activity, mechanism of action, and synergism in combination therapy were investigated for a series of polycyclic amine derivatives. Compound selection was based on the presence of moieties with possible antimycobacterial activity, the inclusion of bulky lipophilic carriers to promote intracellular accumulation, and previously demonstrated bioactivity that potentially support inhibition of efflux pump activity. The most potent antimycobacterial demonstrated a minimum inhibitory concentration (MIC99) of 9.6 μM against Mycobacterium tuberculosis H37Rv. Genotoxicity and inhibition of the cytochrome bc1 respiratory complex were excluded as mechanisms of action for all compounds. Inhibition of cell wall synthesis was identified as a likely mechanism of action for the two most active compounds (14 and 15). Compounds 5 and 6 demonstrated synergistic activity with the known Rv1258c efflux pump substrate, spectinomycin, pointing to possible efflux pump inhibition. For this series, the nature of the side chain, rather than the type of polycyclic carrier, seems to play a determining role in the antimycobacterial activity and cytotoxicity of the compounds. Contrariwise, the nature of the polycyclic carrier, particularly the azapentacycloundecane cage, appears to promote synergistic activity. Results point to the possibility of combining an azapentacycloundecane carrier with a side chain that promotes antimycobacterial activity to develop dual acting molecules for the treatment of Mycobacterium tuberculosis.
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    Competition in the radioisotopes market: evaluation and analysis of drivers which affect mo-99 market share
    (Universty of the Western Cape, 2023) Moremi, Lesedi Maiphepi; Kapp, Erika
    This research aims to evaluate competition in the radioisotopes market and to analyze drivers that affect the market share of radioisotopes, particularly Molybdenum 99 (Mo-99), the most widely used radioisotope in medical procedures. Radioisotopes are safe radioactive substances used globally primarily for diagnosing and treating medical conditions (e.g. oncology, cardiology, thyroid disorders, and neurology). These radioactive substances include, but are not limited to Mo-99, Iodine-131 (I-131), Lutetium 177 non-carrier-added (Lu-177 n.c.a.) & Fluorine-18 (F-18)), that are used as Active Pharmaceutical Ingredients (APIs) for the manufacture of radiopharmaceuticals. The most prevalent diagnostic radioisotope among these fission isotopes, Mo-99, which is used to create Technetium-99m(Tc-99m), is estimated to be utilized in roughly 85% of nuclear medicine diagnostic scans carried out globally (National Academies Press, 2009).
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    Cost-Effectiveness of selecting an Enantiopure formulation over a racemic mixture
    (University of the Western Cape, 2017) Lekuni, Olivia; Kapp, Erika
    The aim of this study is to provide more information in terms of the cost-effectiveness of selecting an enantiopure formulation over a racemic mixture in the context of promoting rational use of medicines. This was done by comparing costs and efficacy of escitalopram versus citalopram and esomeprazole versus omeprazole since they are the most commonly used medicines with both racemate and enantiopure products registered.
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    Discovery of 9-phenylacridinediones as highly selective butyrylcholinesterase inhibitors through structure-based virtual screening
    (Elsevier, 2020) Joubert, Jacques; Kapp, Erika
    Butyrylcholinesterase (BuChE) is considered a promising drug target as it plays an important role in the pro-gression of late stage Alzheimer’s disease (AD). Two compound libraries were selected and 64 124 aminecontaining moieties were screened using a hierarchical virtual screening protocol to discover new selectiveBuChE inhibitors. From these and subsequent docking experiments, 9-phenylacridinedione (9-PAD) was iden-tified as a promising scaffold for selective inhibition of BuChE. Selected top dock scored 9-PADs were assayedand compounds3and6exhibited potent and highly selective human BuChE inhibition (IC50: 98 nM and 142 nM,respectively). Both molecules were also predicted to show sufficient brain permeability, not have any substantialtoxicities, especially hepatotoxicity, and no significantinvitrocytotoxicity against SH-SY5Y neuroblastoma cellsat concentrations up to 100 μM. These findings indicate that 9-PAD is a promising lead structure for the de-velopment of agents able to treat late stage AD.
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    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.
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    Small molecule efflux pump inhibitors in Mycobacterium tuberculosis: a rational drug design perspective
    (Bentham Science Publishers, 2018) Kapp, Erika; Malan, Sarel F.; Joubert, Jacques; Sampson, Samantha L.
    Drug resistance in Mycobacterium tuberculosis (M. tuberculosis) complicates management of tuberculosis. Efflux pumps contribute to low level resistance and acquisition of additional high level resistance mutations through sub-therapeutic concentrations of intracellular antimycobacterials. Various efflux pump inhibitors (EPIs) have been described for M. tuberculosis but little is known regarding the mechanism of efflux inhibition. As knowledge relating to the mechanism of action and drug target is central to the rational drug design of safe and sufficiently selective EPIs, this review aims to examine recent developments in the study of EPIs in M. tuberculosis from a rational drug development perspective and to provide an overview to facilitate systematic development of therapeutically effective EPIs. Review of literature points to a reduction in cellular energy or direct binding to the efflux pump as likely mechanisms for most EPIs described for M. tuberculosis. This review demonstrates that, where a direct interaction with efflux pumps is expected, both molecular structure and general physicochemical properties should be considered to accurately predict efflux pump substrates and inhibitors. Non-competitive EPIs do not necessarily demonstrate the same requirements as competitive inhibitors and it is therefore essential to differentiate between competitive and non-competitive inhibition to accurately determine structure activity relationships for efflux pump inhibition. It is also evident that there are various similarities between inhibitors of prokaryotic and eukaryotic efflux pumps but, depending on the specific chemical scaffolds under investigation, it may be possible to design EPIs that are less prone to inhibition of human P-glycoprotein, thereby reducing side effects and drug-drug interactions.