Browsing by Author "Somandi, Khonzisizwe"

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Synthesis and biological evaluation of pyrimidine and isoquinoline inhibitors as potential antimalarial antifolates and transmission-blocking agents
(2024) Somandi, Khonzisizwe
Malaria continues to be a serious threat, in particular to the African region. According to the World Health Organisation, in 2021, 247 million malaria cases were reported globally of which 95 % and 96 % of malaria related deaths were in the African region. The persistence of the disease, amongst it being difficult to treat and kill, is also attributed to its resistance to currently used antimalarial agents, including class II antifolate drugs such as pyrimethamine, which are used to target the P. falciparum dihydrofolate reductase (PfDHFR) enzyme. However many other drugs have lost activity because of mutations in the active site of the enzyme. The first component of the research described herein has been to synthesise 2,4- diaminopyrimidine analogues that work by disrupting folate metabolism by inhibiting PfDHFR. In a four step synthetic approach we have successfully prepared a series of pyrimidine-2,4-diamines possessing a flexible four atom linker at the 5-position of the pyrimidine ring (in yields of 33-96 %), which could prove advantageous in avoiding clashes with mutant amino acids in the enzyme active site. Enzyme inhibition assays of the compounds have shown successful inhibition of the wild-type (WT) and quadruple mutant (QM) PfDHFR in nM ranges (Ki-WT; 1.27 – 242.72 nM and Ki-QM; 13.01 – 208.23 nM). A moderate antiplasmodial activity in vitro was observed for all compounds assessed against the drug sensitive strain IC50 (TM4/8.2) 0.42 – 28.0 µM and the drug resistant strain IC50(V1S) 3.72 – 53.7 µM. The second component of the research focuses on the synthesis of transmission-blocking analogues that target the sexual stage of the malaria parasite life cycle and work by inhibiting stage IV/V gametocytes which prevents the transmission of the parasite from the human host back to the feeding mosquito. A series of 3-substituted-isoquinolin-1-yl benzamides, derivatives of the hit compound MMV1581558, have been successfully prepared in a synthetic protocol that involves only two steps from relatively simple precursors, in yields ranging between 14 – 68 %. All analogues are undergoing biological assessment against stage IV/V gametocytes and currently we have only received the results of the asexual blood stage activity assay, with most analogues displaying only moderate activity (IC50 1.18 – 7 µM). Additional biological assays are still underway
The wound healing effect of exosomes derived from Lobostemon fruticosus
(University of the Witwatersrand, Johannesburg, 2024) Rajcoomar, Yashmika; Somandi, Khonzisizwe
Exosomes are increasingly being researched and recognized as a novel mode of intercellular communication which can potentially play a significant role in many cellular processes, including immune responses, signal transductions and antigen presentation. Exosomes are membrane bound nanovesicles produced by both mammalian and plant cells. Developing research is mainly focused on their ability to act as a drug delivery vehicle. Other research interests around exosomes are their therapeutic effects for many common diseases including cancer and chronic inflammation. Plant-derived exosomes have emerged as potential candidates for many clinical and therapeutic applications. The aim of this project was to isolate exosomes derived from Lobostemon fruticosus leaves and to investigate the wound healing potential from this plant species. The plant-derived exosomes were isolated by ultracentrifugation and were characterised by means of scanning electron microscopy (SEM), ZetaSizer, Energy-dispersive Xray spectroscopy and the Pierce™ BCA Protein Assay Kit. The wound healing potential was assessed by In vitro scratch assay using human keratinocytes (HaCaT). The exosomes displayed a round, spherical shape and had diameters ranging from 41 to 67 nm – falling within range of nano-sized exosomes. The exosomes had a mean particle size of 166.2 d.nm. Chemical analysis of the samples using energy dispersive spectroscopy revealed the presence of carbon, oxygen, potassium, chloride, gold, palladium and sodium. The protein quantification results revealed the exosomes were rich in proteins. The cell viability results, using various concentrations of Lobostemon fruticosus exosomes, revealed non-cytotoxicity on HaCaT cells. The In vitro scratch assay demonstrated that the exosomes enhanced the migration ability of HaCaT cells in a time dependent manner. The findings suggest and reveal that exosomes derived from Lobostemon fruticosus could accelerate the healing process and can be employed as a future drug delivery platform. Further research is required to establish the exact mechanism of action of the healing potential of this plant specie's constituents. Overall results suggest that exosomes derived from Lobostemon fruticosus are promising as a potential agent for skin regeneration