Browsing by Author "Jardine, Anwar"

Now showing 1 - 8 of 8
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    The design, synthesis and characterization of polynuclear materials for applications for catalysis
    (2012) Makhubela, Banothile Charity Events; Smith, Gregory S; Jardine, Anwar
    The synthesis and characterization of new chitosan- and 6-deoxy-6-amino chitosan-supported ligands is discussed. This was achieved via the reaction of either 2-pyridinecarboxaldehyde or 2-(diphenylphosphino)benzaldehyde with the accessible amino groups of chitosan to afford chitosan-supported Schiff base ligands (2.1-2.4) bearing iminopyridyl and iminophosphine functionalities on the surface. Complexation reactions with [PdCl2(COD)] and [RhCl(CO)2]2 gave the corresponding chitosan-supported complexes (2.5-2.8) and (2.13-2.14). These metal-containing materials and their precursors were isolated as air and moisture stable solids which proved insoluble in common organic solvents and have been characterized analytically and spectroscopically...
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    Investigating the Interaction of Chitin in Organic Electrolyte Solutions Using Molecular Dynamics
    (2019) Carroll, Lenard Leslie; Venter, Gerhard; Jardine, Anwar
    The dissolution, hydrolysis and fermentation of biopolymers afford biofuels, an alternative source of energy. Unfortunately, biopolymers have hydrogen bonding networks that are difficult to disrupt and dispersion forces to overcome, all of which make it insoluble in most common organic solvents and water under moderate conditions. Much work has been devoted to improving the dissolution of biopolymers, via alternative solvents or by developing new ground-breaking processes. One alternative solvent that has become quite popular in biomass dissolution studies are ionic liquids (ILs). Ionic liquids are attractive solvents due to its broad range of uses and advantageous properties. ILs have been promising in its use in separation, extraction, catalysis, lubricants, fuel cells, batteries and liquid crystal research. ILs also have low vapour pressure, which implies low toxicity with respect to their clean-up. While many ILs are produced under environmentally unfriendly conditions, more studies are being done on finding ways to synthesise these species using the 12 design principles of Green Chemistry. While a plethora of studies has been done on the experimental dissolution of cellulose in ionic liquids, similar studies have been minimal for chitin. As such, a computational investigation on the dissolution of chitin in ionic liquids and organic electrolyte solutions (OESs) is presented here. OESs consists of an ionic liquid and an additional aprotic organic molecular solvent, known henceforth as a co-solvent. These mixtures are considered as some ILs have high viscosities, which decreases its ability to effectively dissolve biopolymers, but by adding co-solvents to the IL, the mixture’s viscosity decreases, potentially improving on the solubility of the biopolymer. Computationally, the dissolution of chitin was modelled through molecular dynamics simulations as implemented in the AMBER MD code, by studying the separation of two 4-methyl-β-D-Nacetylglucosamine-(1→4’)-1’-methyl-β-D-N’-acetylglucosamine ((GlcNAc)2Me2) molecules (chosen as the model for chitin) in various solvent systems using potential of mean force calculations. The ionic liquids of choice were 1-butyl-3-methylimidazolium acetate ([C4C1im][CH3COO]) and 1-butyl3-methylimidazolium methyl sulfate ([C4C1im][CH3SO4]), two ILs that have experimental physical properties available, a requirement for MD simulation validation. The co-solvents chosen were dimethyl carbonate, propylene carbonate and γ-valerolactone, three structurally similar bio-based solvents. The solvation of a (GlcNAc)2Me2 monomer was also studied in this project via radial distribution functions, interaction energies and hydrogen bond analyses, as to support the results produced from the separation study. Additionally, the experimental swelling of chitin was investigated as to compare it to the interaction energy results, acting as further validation of the computational results. The computational results suggest that the (GlcNAc)2Me2 monomer will interact more favourably with pure [C4C1im][CH3COO], followed by the 8:2 [C4C1im][CH3COO]:co-solvent OESs, the 2:8 [C4C1im][CH3COO]:co-solvent OESs and then the pure co-solvents. The solvation study agrees with this trend. The PMF results also show that a (GlcNAc)2Me2 dimer will separate spontaneously in all the solvent systems, with the least amount of thermodynamic work required (to separate) in pure [C4C1im][CH3COO], and the most in pure dimethyl carbonate.
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    Non-Neuroleptic Antitubercular and Anticancer Therapeutics through Rational Drug Remodelling of Phenothiazines and Related Antipsychotics
    Semenya, Manare Molahlegi Dorothy; Jardine, Anwar
    In light of shrinking pharmaceutical drug pipelines and drug resistance, innovative drug discovery strategies are of imperative need. Drug repurposing and related strategies such as drug rescue and drug remodelling have garnered significant research interest. Various clinically approved non-antibiotics including phenothiazines hold promise as novel classes of therapeutics in other indications. However, in addition to inherent neuroleptic properties, phenothiazines and related antipsychotics elicit adverse side effects at clinically relevant doses thus precluding their extensive clinical application. Herein, it was postulated that the selectivity of phenothiazines and related drugs for nonneuroleptic indications could be enhanced through rationalized structural remodelling. Phenothiazine and related neuroleptics are known to obey a lipophilic chromophore/basic side chain paradigm. Deviation from this paradigm is expected to decrease potential for neuroleptic effects. Therefore, the remodelling strategies involved introduction of novel functionalities that are dissimilar to native phenothiazine structures. Prior to chemical synthesis, drug metabolism and pharmacokinetic related properties were predicted in silico to assess drug-likeness of the new chemical entities derived from phenothiazines and related antipsychotics. The in silico profiling also included prediction of blood/brain partition coefficients and CNS activity to determine their likelihood of exhibiting neuroleptic effects. The new chemical entities were then evaluated against drug-susceptible Mycobacterium tuberculosis-H37Rv. Furthermore, a selected series was screened for binding to dopamine and serotonin receptors to corroborate in silico CNS activity predictions. Moreover, pharmacokinetic studies were conducted with the selected series to determine in vitro microsomal stability, kinetic solubility and in vivo toxicity profiles. Another objective of this study was to evaluate the new chemical entities for their potential as anticancer agents. The key findings herein demonstrated that it is possible to abolish neuroleptic effects through rationalized structural manipulation and still retain bio-activities of interest. Several new chemical entities including N-alkylsulfonates (DS0031, DS0032, DS0034, DS0035, DS00366) and nitrobenzenesulfonamides (DS00325, DS00326, DS00329) of phenothiazines, displayed notable antitubercular (GAST/Fe MIC90 range: 9.9-125 µM; 7H9 MIC range 12.5- 25 µg/mL) and anticancer (IC50 range 4.51-12.43 µM) activities in comparison to native phenothiazine drugs. Furthermore, in vitro and in vivo preclinical evaluation revealed favourable pharmacokinetic profiles. Overall, this study presents novel subclasses of phenothiazines that hold promise for further development as non-neuroleptic agents in either tuberculosis or cancer treatment regimens.
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    Remediation of water using modified chitosan.
    (2013) Sayed, Shakeela; Jardine, Anwar
    Water treatment has been an area of increasing concern over the last decade. This interest is due to exponential increase in demand of already limited water sources. Therefore the treatment of wastewater for re-use is a topic of great interest. The treatment applied depends on the source and quality of the water. Common water treatment options include filtration, flocculation, coagulation, lime softening, reverse osmosis and clarification to name a few. In addition, water should also be treated for the presence of harmful micro-organisms which is normally done using chlorine-based disinfection. Water purification filters which purify water by removal of impurities and micro-organisms are in great demand. Therefore the aim of this study was to develop ion exchange polymers and antimicrobial filters using ‘green’ materials.
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    Synthesis and evaluation of flouro and thia lipids as bioanalytical tools
    (2014) Manuel, Gaynor; Jardine, Anwar; Chibale, Kelly
    Lipid catabolism plays a significant role in the survival of M.tb inside the host. The development of analytical techniques such as gas chromatography mass spectroscopy (GCMS) and liquid chromatography mass spectroscopy (LC-MS) has become popular as metabolomics tools in the study of such catabolic pathways. The development of biomarkers and internal standards to perform quantitative and qualitative analysis of metabolites in the catabolic pathway would be an attractive tool. Thus, cholesterol derivatives were synthesized as thia-, fluoro- and deuterium labeled analogs. Sulfur was incorporated into cholesterol at positions, C3 as well as C23. The 3â-mercaptocholest-5-ene was synthesized to block the initial stage of cholesterol catabolism and evaluate whether side chain degradation can still occur. Fluorine was integrated into the cholesterol backbone at C3 to evaluate the side-chain degradation in the absence of cholesterol oxidase activity. Steroids with fluorine at C6 are known to have good biological activity and were for this reason also synthesized. Deuterium labeled compounds were synthesized and used as internal standards for GC-MS analysis. As an alternative to cholesterol catabolism, fatty acids like stearic acid are important in producing building blocks for long chain mycolic acids which provides protection to the mycobacterium. For this reason thiastearic acid derivatives were synthesized and evaluated as biomarkers.
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    Synthesis and evaluation of M.tb Glycosyltransferase (MshA) inhibitors
    (2014) Sehata, Majimi James; Jardine, Anwar
    The emergence of multiple drug resistant (MDR) and extremely drug resistant (XDR) strains of Mycobacterium tuberculosis (M.tb) against the known anti-tuberculosis drug regimens has prompted the need to search for new anti-tubercular drugs. In this study we report the design and synthesis of a series of thiazolidinethione derivatives and substrate mimics, aimed at targeting the mycothiol biosynthetic pathway which is specific to mycobacteria. The strategy involved design of molecules that are expected to compete for the UDP-GlcNAc binding site of the glycosyltransferase (MshA) of M.tb. The bioactivity of the designed molecules against M.tb in cell free and whole cell assays serves as a basis for further inhibitor optimisation. Amongst the thiazolidinethione derivatives screened, compounds (Z)-5-(2,4-dichlorobenzylidene)-2-thioxothiazolidin-4-one (MJ3A) and 2-((Z)-5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (MJ7B) were found to be the most potent compounds with a MIC 50 of 10 μg/mL. In addition, substrate mimics were synthesized and screened for anti-tuberculosis activity. Substrate mimics displayed moderate activity, with exception of substrate mimic (4 -34) which displayed th e highest potency. Tunicamycin which is a known glycosyltransferase inhibitor displayed the highest potency against M.tb H37Rv whole cells by inhibiting cell growth with a MIC 50 of 5 μg/mL . Tunicamycin inhibits the transfer of GlcNAc-1-P from UDP-GlcNAc to polyprenyl monophosphates in a variety of organisms including Gram positive bacteria.
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    Synthesis of Mycobacterial Ergothioneine biosynthetic pathway metabolites
    (2013) Khonde,Lutete Peguy; Jardine, Anwar
    Many gram positive bacteria, such as Mycobacterium tuberculosis, lack the redox protective molecule, glutathione and produce mycothiol (MSH) and ergothioneine (ESH) as their principal low molecular mass thiol instead. Ergothioneine has been known for a while as an anti-oxidant; however its role as a protective thiol in Mycobacterium tuberculosis is still undefined. Present knowledge indicates that ergothioneine may play a critical role in the in vivo and in vitro survival of Mycobacteria, hence enzymes involved in ESH synthesis can be considered as potential drug targets. Ergothioneine is synthesized by the sequential action of five enzymes, encoded by the genes egtA, egtB, egtC, egtD and egtE. Three of these enzymes implicated in the ergothioneine synthesis have been expressed and purified. The last step catalyzed by EgtE, a pyridoxal 5-phosphate (PLP)-dependent β-lyase convert the S-(β-amino-β-carboxyethyl) ergothioneine sulfoxide to ergothioneine. This thesis describes the synthesis of ESH pathway enzyme substrates, with the main focus on the synthesis of the EgtE enzyme substrate, ESH biosynthetic precursor, R- and S-(β-amino-β-carboxyethyl) ergothioneine sulfoxide. In order to prove that synthesized compounds are indeed mycobacterium ESH pathway enzyme substrates, crude M. smeg cell free lysate enzyme was used to convert substrates to ESH. Enzymatic transformation was followed by LCMS analysis. One of two synthetic routes studied, required sufficient quantities of ESH and were therefore thoroughly reviewed. An improved synthetic procedure for ESH was obtained. Deuterated hercynine and ESH was prepared, which will serve as a valuable internal standards and probes for ergothioneine metabolic studies. Enantioselective sulfoxidation of EgtE enzyme substrate precursor, hercynyl cysteine sulfide gave the required hercynyl cysteine sulfoxide derivative and in same cases the hercynyl cysteine sulfone. Crude enzyme mediated transformation of substrates indicated that the hercynyl cysteine sulfide undergoes efficient conversion to ESH.
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    The anti-cancer activity of extracts derived from millets and Kraalbos
    (2020) Mohamed, Luqmaan; Prince, Sharon; Jardine, Anwar; Chakraborty, Suparna
    Breast cancer is the second most commonly diagnosed cancer and the leading cause of cancer deaths in women. Several factors, such as the costs of anti-cancer drugs, drug resistance and relapse, make it difficult to treat this disease effectively. In the South African context this is exacerbated by poor socio-economic conditions. Thus, there is a dire need to develop novel anti-breast cancer drugs which are safe, effective and cheap. In this regard, natural products serve as a highly exploitable medicinal resource and indeed, many successful commercially available drugs have been derived from natural products. Plants, especially those used as food or medicine, are a particularly robust source of beneficial phytochemicals. Thus, this study investigated the anti-cancer effects of extracts derived from three varieties of African millets as well as from the indigenous Kraalbos plant, Galenia africana, against the MCF-7 oestrogen receptor positive and the MDA-MB-231 triple negative breast cancer cell lines. The millet extracts tested were derived from Sorghum bicolor (Enforcer), Pennisetum glaucum (Babala) and Eragrostis tef (Tef) using both a reflux-based and a cold extraction procedure. MTT assays reveal that the millet extracts derived from the reflux-based extraction show no short-term cytotoxicity against both breast cancer cell lines tested. Extracts derived from the cold extraction were subjected to fractionation using HPTLC. Results from these extracts show that only the methanol fractions of the Babala and Enforcer millets exhibited short-term cytotoxic activity against the MCF-7 and the MDAMB- 231 breast cancer cell lines. Five Kraalbos extracts (KB1, KB2, KB3, KB4 and KB5) were tested for their short-term cytotoxicity against the MCF-7 and MDA-MB-231 breast cancer cell lines. KB2 was found to display the most potent activity and its anti-cancer activity was characterized further. Clonogenic assays revealed that KB2 also displayed long-term cytotoxicity against breast cancer cells but not normal breast epithelial cells. Scratch motility assays and western blotting with antibodies to epithelial to mesenchymal transition markers showed that KB2 inhibited the migratory ability of breast cancer cells. To understand the mechanism(s) underpinning the anti-cancer activity of KB2, ROS-GloTM H2O2 and GSH-GloTM Glutathione assays were performed and the results revealed that KB2 induced the production of reactive oxygen species. Furthermore, western blotting with antibodies to γH2AX showed that KB2 induced double strand DNA breaks in breast cancer cells. Flow cytometry and western blotting with antibodies to p53, p21, cyclin A and cyclin B1 further revealed that KB2 causes breast cancer cells to arrest in the S and G2/M phases. A sub-G1 peak, indicative of cell death, was also observed in the flow cytometry analyses. Indeed, using western blotting with antibodies to markers of apoptosis (caspases 3, 7, 8, and 9 and PARP) and necroptosis (p-MLKL and p-RIP3) KB2 was found to induce cell death via the intrinsic and extrinsic apoptotic pathways and necroptosis. Western blotting and immunocytochemistry with an antibody to LC-3 also showed that KB2 induces autophagy in the breast cancer cells but whether it functions as a pro-death or pro-survival mechanism remains to be elucidated. Taken together, this study demonstrates that extracts derived from millets and Kraalbos show anti-cancer activity against oestrogen receptor positive and triple negative breast cancer cells and that KB2 is worth progressing to pre-clinical studies.