Masters Degrees (Molecular Biology and Human Genetics)

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Browsing Masters Degrees (Molecular Biology and Human Genetics) by browse.metadata.advisor "Chellan, Prinessa"

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    Ferrocene sulfonyl derivatives as antimycobacterials
    (Stellenbosch : Stellenbosch University, 2024-02) McMaster, Erin Cullen; Mavumengwana, Vuyo; Chellan, Prinessa; Niemand-Wolhuter, Nandi; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics.
    ENGLISH ABSTRACT: Tuberculosis (TB) remains a global health threat, necessitating innovative strategies to combat Mycobacterium tuberculosis, the causative agent. This thesis explores the multifaceted approach of developing ferrocene-based compounds as potential antimycobacterial agents. Macrophages, critical components of the host's defense against M. tuberculosis, serve as the initial battleground for M. tuberculosis infection. The bacterium adeptly manipulates host defences, thriving within macrophages and evading immune responses. Targeting mycobacteria within macrophages is crucial for successful treatment, minimizing host tissue damage, and modulating the immune response effectively. The study capitalizes on the dependence of mycobacteria on iron, a crucial element for its survival within macrophages. Ferrocene, known for its lipophilic properties, was conjugated with a selected range of sulfonamides to realise novel ferrocene sulfonamide derivatives. The latter were subjected to extensive analysis, including nuclear magnetic resonance (NMR), infrared spectroscopy (FT-IR), mass spectrometry (ESI-MS), and high-performance liquid chromatography (RP-HPLC). UV-Vis spectroscopy revealed stability concerns, prompting considerations for improving solubility and bioavailability. Turbidimetric studies highlighted poor solubility in aqueous environments, emphasizing the need for advanced delivery systemsin future studies. Microbiological assessments, including Minimum Inhibitory Concentration (MIC) experiments, shed light on the compounds' effectiveness against Mycobacterium smegmatis mc2155. The most effective derivative showed an MIC of 0.0039 – 0.00195 mg/mL compared to >0.26, >0.30, and >0.49 from derivatives ferrocene benzene sulfonyl hydrazide (P1), ferrocene ptoluene sulfonyl hydrazide (P2), and ferrocene trifluoromethyl sulfonyl hydrazide (P3) respectively. Intriguingly, certain derivatives demonstrated potential growth-promoting effects, indicating an intricate relationship between ferrocene compounds and mycobacterial growth. The ferrozine assay, assessing intracellular iron levels, suggested a dynamic interaction between mycobacteria and the ferrocene derivatives, with fluctuations in iron absorption during the growth curve. The final component of the study involved evaluating cytotoxicity on THP-1 cells, where ferrocene benzene sulfonyl hydrazide (P1), ferrocene p-toluene sulfonyl hydrazide (P2), ferrocene trifluoromethyl sulfonyl hydrazide (P3) and the ferrocene-RP-1 derivative show promise, although further replicates are essential for conclusive results. In conclusion, this thesis presents a comprehensive exploration of ferrocene-based compounds as potential antimycobacterial agents. The findings underscore the complexity of the interactions, necessitating a nuanced approach for drug development. Addressing solubility challenges and further elucidating the mechanisms underlying seeming sustenance of growth but intracellular disruptions as observed through scanning electron microscopy could pave a way for novel therapeutic strategies against tuberculosis.