Ferrocene sulfonyl derivatives as antimycobacterials

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dc.contributor.advisorMavumengwana, Vuyoen_ZA
dc.contributor.advisorChellan, Prinessaen_ZA
dc.contributor.advisorNiemand-Wolhuter, Nandien_ZA
dc.contributor.authorMcMaster, Erin Cullenen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics.en_ZA
dc.date.accessioned2024-02-15T08:34:58Zen_ZA
dc.date.accessioned2024-04-27T00:53:52Zen_ZA
dc.date.available2024-02-15T08:34:58Zen_ZA
dc.date.available2024-04-27T00:53:52Zen_ZA
dc.date.issued2024-02en_ZA
dc.descriptionThesis (MSc)--Stellenbosch University, 2024.en_ZA
dc.description.abstractENGLISH 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.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Tuberkulose (TB) bly 'n wêreldwye gesondheidsbedreiging, wat innoverende strategieë benodig om Mycobacterium tuberculosis, te beveg. Hierdie proefskrif ondersoek die benadering van die ontwikkeling van ferroseen-gebaseerde verbindings as potensiële anti-mikobakteriële middels. Makrofage, ‘n kritieke komponent van die infekteerde gas se verdediging teen TB, dien as die aanvanklike area vir M. tuberculosis-infeksie. Bakterieë manipuleer die infekteerde gasheer se verdediging, en floreer dan binne makrofage en ontwyk die immuunreaksie. Vir behandeling om suksesvol te wees, is dit van kritieke belang om mikobakterieë binne makrofage te teiken. Behandeling moet weefselskade beperk en terselfdertyd ʼn doeltreffende immuun reaksie stimuleer. Die studie trek voordeel uit die feit dat mikobakterieë afhanklik is van yster, 'n kritieke element vir hul oorlewing binne in makrofage. Ferroseen, bekend vir sy lipofiliese eienskappe, is aan 'n geselekteerde reeks sulfonamiede verbind om nuwe ferroseen-sulfonamied variante te lewer. Laasgenoemde gaan deur ekstensiewe analises, insluitend kern magnetiese resonansie, infrarooi spektroskopie, massa spektrometrie en hoë-prestasie vloeistofchromatografie. UVsigbare spektroskopie het stabiliteitskwessies aan die lig gebring ten opsigte van verbeterde oplosbaarheid en biobeskikbaarheid. Turbidimetriese studies het swak oplosbaarheid in waterige omgewings beklemtoon, wat die noodsaaklikheid van gevorderde afleweringsisteme in toekomstige studies beklemtoon. Mikrobiologiese assesserings, insluitend minimum inhiberende konsentrasie eksperimente, het lig geskyn op die verbindings se doeltreffendheid teen Mycobacterium smegmatis. Die mees doeltreffende variant het 'n minimum inhiberende konsentrasie van 0.0039 – 0.00195 mg/mL getoon in vergelyking met >0.26, >0.30, en >0.49 van die ferroseenbenseen-sulfoniel-hidrazied (P1), ferroseen p-tolueensulfoniel-hidrazied (P2) en ferroseen trifluorometielsulfoniel-hidrazied (P3) variante, onderskeidelik. Interessant genoeg het sekere variante potensiële groei-bevorderende effekte getoon, wat 'n ingewikkelde verband tussen ferroseen variante en mikobakteriese groei aandui. Die ferrozien-toets, wat intrasellulêre ystervlakke assesseer, het op 'n dinamiese interaksie tussen mikobakterië en die ferroseen variante gedui, met fluktuasies in yster absorpsie. Die finale komponent van die studie behels die evaluering van sitotoksisiteit op THP-1-selle, waar ferroseenbenzeensulfoniel-hidrazied (P1), ferroseen p-tolueensulfoniel-hidrazied (P2), ferroseen trifluorometielsulfoniel-hidrazied (P3) en die ferroseen-RP-1-derivaat belowende resultate getoon het, alhoewel verdere herhalings noodsaaklik is vir ʼn konkrete afleiding.af_ZA
dc.description.versionMastersen_ZA
dc.format.extent111 pages : illustrationsen_ZA
dc.identifier.urihttps://scholar.sun.ac.za/handle/10019.1/130638en_ZA
dc.language.isoen_ZAen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshMycobacterium tuberculosisen_ZA
dc.subject.lcshFerroceneen_ZA
dc.subject.lcshSulfonamides -- Therapeutic useen_ZA
dc.subject.lcshMacrophages en_ZA
dc.subject.lcshDrug developmenten_ZA
dc.titleFerrocene sulfonyl derivatives as antimycobacterialsen_ZA
dc.typeThesisen_ZA
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