Development of new antimalarial ferrocenyl-artesunate complexes

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dc.contributor.advisorChellan, Prinessaen_ZA
dc.contributor.authorMunnik, Brandon Liamen_ZA
dc.contributor.otherStellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.en_ZA
dc.date.accessioned2023-03-03T12:15:32Zen_ZA
dc.date.accessioned2023-05-18T07:18:15Zen_ZA
dc.date.available2023-03-03T12:15:32Zen_ZA
dc.date.available2023-05-18T07:18:15Zen_ZA
dc.date.issued2023-03en_ZA
dc.descriptionThesis (MSc)--Stellenbosch University, 2023.en_ZA
dc.description.abstractENGLISH ABSTRACT: Despite declining numbers over the past 20 years, malaria, which is caused by the parasite Plasmodium falciparum, remains a serious issue in many parts of the world, especially in Africa. This problem is further exacerbated by the arrival of the COVID-19 pandemic, which led to difficulties in service delivery to third-world countries. The World Health Organization shifted to the use of artemisinin-based combination therapy in order to counteract increasing resistance to chloroquine. However, as of 2004, resistance to artemisinin-based combination therapy has been on the rise. Organometallic drugs have shown promise in combatting malaria strains that are resistant to chloroquine, a previously used quinoline based drug. Ferroquine is a ferrocene containing chloroquine hybrid, which has made it to phase II clinical trials and is a prime example of improving activity through metal conjugation. Artesunate (Ars), a derivative of artemisinin, is a semisynthetic antimalarial drug and forms part of the artemisinin-based combination therapy arsenal. The drug functions mainly by activation of its endoperoxide bridge leading to increased oxidative stress in malaria parasites. The goal of this project was to prepare four ferrocenyl containing artesunate derivatives to explore the effects of combining the two moieties. The complexes were all obtained in moderate yields with high purity and characterized by 1H and 13C{ 1H} NMR spectroscopy as well as electrospray ionisation mass spectrometry and the redox profiles were examined using cyclic voltammetry. All the complexes demonstrated good activity against the model Apicomplexa Toxoplasma gondii (T. gondii) with IC50 values in the low micromolar range (0.28-1.2 µM). T. gondii was further used to investigate a potential mode of action (MoA). It was determined that the mode of action for the MoA of the organometallic conjugates was through the generation of reactive oxygen species, the same as that of the parent drug, artesunate. However, in the case of the artesunate-ferrocenyl ethyl amide (C3) a novel mechanism of death to the parasite was observed using immunofluorescence microscopy. All complexes showed good to excellent antimalarial Stellenbosch University https://scholar.sun.ac.za iii activity against the chloroquine sensitive strain of Plasmodium falciparum (P. falciparum, NF54), with IC50 values ranging from 12 to 4858 nM. The complexes all showed low cytotoxicity towards the two healthy cell lines tested – Human embryonic kidney (HEK293) and Human prostatic cells (PNT1A) – and high selectivity for T. gondii over healthy cells. Future work will involve testing the complexes as potential anticancer agents and further looking into the novel mechanism of action demonstrated by the artesunate-ferrocenyl ethyl amide (C3). This could potentially be done by attaching a fluorescent probe to the drug and monitoring where the drug accumulates.en_ZA
dc.description.abstractAFRIKAANS OPSOMMING: Tenspyte die dalende getalle oor die afgelope 20 jaar bly malaria, wat deur die parasiet Plasmodium falciparum veroorsaak word, 'n ernstige probleem in baie dele van die wêreld, veral in Afrika. Hierdie probleem was vererger deur die COVID-19-pandemie, wat gelei het tot probleme met dienslewering aan derdewêreldlande. Die Wêreldgesondheidsorganisasie (WHO) het oorgeskakel na die gebruik van artemisinien-gebaseerde kombinasieterapie om toenemende weerstand teen chlorokien teë te werk. Vanaf 2004 het weerstand teen artemisinien-gebaseerde kombinasieterapie egter begin ontwikkel. Organometaalmiddels het belofte getoon in die bekamping van malaria-stamme wat bestand is teen chlorokien, 'n voorheen gebruikte kinolien-gebaseerde middel. Ferrokien is 'n ferroseenbevattende chlorokienbaster, wat tot fase II kliniese proewe gehaal het en 'n uitstekende voorbeeld is van die verbetering van aktiwiteit deur metaal byvoeging. Artesunaat, 'n afgeleide verbinding van artemisinien, is 'n semisintetiese antimalariamiddel en vorm deel van die artemisiniengebaseerde kombinasieterapie-arsenaal. Die middel funksioneer hoofsaaklik deur die aktivering van sy endoperoksiedbrug wat lei tot verhoogde oksidatiewe stres in die malariaparasiet. Die doel van hierdie projek was om vier ferrosenielbevattende artesunaatderivate voor te berei. Die komplekse is almal verkry in matige opbrengste met hoë suiwerheid en gekenmerk deur 1H en Stellenbosch University https://scholar.sun.ac.za iv 13C KMR spektroskopie sowel as elektrosproei ionisasie massaspektrometrie (ESI-MS) en die redoks profiele was geondersoek met behulp van sikliese voltammetrie. Al die komplekse het goeie aktiwiteit getoon teen die model Apicomplexa Toxoplasma gondii met IC50 waardes in die lae mikromolêre reeks (0.2836-1.175 µM). T. gondii is verder gebruik om 'n potensiële werkingswyse te ondersoek wat bevind het dat die werking van die organometaalkonjugate as gevolg is van die generering van reaktiewe suurstofspesies nes in die geval met die moedermiddel, artesunaat. In die geval van artesunate-ferrocenyl etielamied (C3) is 'n nuwe meganisme van dood aan die parasiet egter waargeneem, met behulp van immunofluoressensiemikroskopie. Die vier komplekse het almal goeie tot uitstekende antimalariale aktiwiteit getoon teen die chlorokien sensitiewe stam van P. falciparum, NF54, met IC50 waardes wat wissel van 12 tot 4858 nM. Die komplekse het almal lae sitotoksisiteit teenoor die twee gesonde sellyne wat getoets is (HEK293 en PNT1A) en hoë selektiwiteit vir T. gondii oor gesonde selle getoon. Toekomstige werk sal die toetsing van die komplekse as potensiële teenkankermiddels behels en verder kyk na die nuwe meganisme van werking wat deur die artesunate-ferrocenyl etielamied (C3) gedemonstreer word. Dit kan moontlik gedoen word deur 'n fluoresserende sonde aan die geneesmiddel te heg en te monitor waar die geneesmiddel ophoop. af_ZA
dc.description.versionMastersen_ZA
dc.format.extentxv, 106 pages : illustrationen_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/127363en_ZA
dc.language.isoen_ZAen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshOrganometallic compounds en_ZA
dc.subject.lcshCommunicable diseases -- Alternative treatment en_ZA
dc.subject.lcshPlasmodium falciparumen_ZA
dc.subject.lcshAntimalarialsen_ZA
dc.titleDevelopment of new antimalarial ferrocenyl-artesunate complexesen_ZA
dc.typeThesisen_ZA
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