The synthesis and evaluation of new organometallic benzimidazole Complexes as antiplasmodials

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dc.contributor.advisorChellan, Prinessaen_ZA
dc.contributor.authorJordaan, Lydiaen_ZA
dc.contributor.otherStellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.en_ZA
dc.date.accessioned2020-06-01T15:55:30Zen_ZA
dc.date.accessioned2021-02-01T07:54:06Zen_ZA
dc.date.available2020-06-01T15:55:30Zen_ZA
dc.date.available2021-02-01T07:54:06Zen_ZA
dc.date.issued2020-12en_ZA
dc.descriptionThesis (MSc)--Stellenbosch University, 2020.en_ZA
dc.description.abstractENGLISH ABSTRACT: Despite ongoing efforts to discover new antimalarial drugs, malaria remains a serious concern in developing countries due to the widespread resistance of Plasmodium falciparum (P. falciparum) to antimalarial drugs such as chloroquine. Organometallic complexes, particularly those containing platinum group metals have shown great promise for the development of new antimalarial treatments. The majority of antiplasmodial organometallic complexes reported in the literature are derived from quinoline-containing ligands. Benzimidazole is an attractive pharmacophore as it has displayed various pharmacological activities and can bind to a range of biological receptors. Few organometallic complexes of benzimidazoles have been reported, and even fewer that display antimalarial activity. In this study, two known and four new cationic iridium and rhodium complexes were synthesised from 2-(2-pyridyl)benzimidazole and metal dimers with different η5-Cpx groups (x = Me, ph or biph). Six new neutral cyclometallated iridium and rhodium complexes of 2- phenylbenzimidazole were also synthesised, as several C^N cyclometallated complexes reported in the literature have displayed improved biological activities compared to their N^N analogues. All complexes were obtained in moderate to good yields with high purity. The complexes were characterised using infrared and 1H and 13C NMR spectroscopy as well as mass spectrometry. The single crystal X-ray structures of the pyridyl complexes were obtained and confirmed the expected molecular structures. The pyridyl (C1 – C6) and phenyl complexes (C7 – C12) all displayed moderate to good antiplasmodial activity against the CQ-sensitive 3D7 strain of P. falciparum. The pyridyl complexes were also evaluated against the CQ-resistant Dd2 strain and, in general, improved activities were observed compared to 3D7. In general, the rhodium complexes out-performed the iridium complexes in both series and an increase in activity was observed when the cyclopentadienyl group was extended, in the order Cp* < Cpxph < Cpxbiph. This can be attributed to increased hydrophobicity. The cyclometallated rhodium Cpxbiph complex, which is the most active of the cyclometallated complexes, deviates from this trend. The pyridyl complexes exhibited low cytotoxicity to human embryonic kidney (HEK) cells compared to their activity against P. falciparum strains, which is an indication of good selectivity. Future work will involve investigating potential mechanism of action of these complexes, performing further in vitro biological tests on the cyclometallated complexes and potentially modifying the ligand to improve the antimalarial activities of these complexes. Overall, the newly synthesised pyridyl and cyclometallated organometallic complexes are promising candidates for further investigation as potential antimalarial agents.en_ZA
dc.description.abstractAFRIKAANS OPSOMMING: Ten spyte van voortdurende pogings om nuwe anti-malaria middels te ontdek, veroorsaak die wydverspreide weerstand van Plasmodium falciparum (P. falciparum) teen anti-malaria middels soos chloorokien, dat malaria 'n ernstige probleem in ontwikkelende lande bly. Organometaalkomplekse, veral dié wat platinumgroepmetale bevat, het beloftes ingehou vir die ontwikkeling van nuwe antimalaria behandelings. Die meerderheid van anti-plasmodiale organometaalkomplekse wat in navorsing aangemeld is, is afgelei van kinolienbevattende ligande. Benzimidazole is 'n goeie farmakofoor, aangesien dit verskillende farmakologiese aktiwiteite vertoon het en kan verbind met verskeie biologiese reseptore. Min organometaalkomplekse van benzimidazole is gerapporteer en selfs minder is aktief teen malaria. In hierdie studie is twee bekende en vier nuwe kationiese iridiumen rodiumkomplekse gesintetiseer van 2-(2-pyridyl)benzimidazole en metaaldimere met verskillende η5-Cpx-groepe (x = Me, ph of biph). Ses nuwe neutrale siklometaalvormige iridium- en rodiumkomplekse van 2-Phenylbenzimidazole is ook gesintetiseer, aangesien verskeie gerapporteerde C^N-siklometaalkomplekse verbeterde biologiese aktiwiteite getoon het in vergelyking met hul N^N-analoë. Alle komplekse is verkry in matige tot goeie opbrengste en 'n hoë suiwerheid. Die komplekse is gekenmerk deur infrarooi en 1H en 13C KMR-spektroskopie asook massaspektrometrie. Die enkelkristal X-straalstrukture van die piridielkomplekse is verkry en bevestig die verwagte molekulêre strukture. Die piridiel (C1 – C6) en feniel (C7 – C12) komplekse het almal matige tot goeie antiplasmodiale aktiwiteit teen die CQ-sensitiewe 3D7-stam van P. falciparum vertoon. Die piridielkomplekse is ook beoordeel teen die CQ-weerstandige Dd2-stam, en meeste van die komplekse is meer aktief teen hierdie stam in vergelyking met 3D7. Oor die algemeen het die rodiumkomplekse beter as die iridiumkomplekse vir beide reekse gevaar, en 'n toename in aktiwiteit is waargeneem toe die cyclopentadienylgroep uitgebrei is, in die volgorde Cp* <Cpxph <Cpxbiph. Dit kan toegeskryf word aan verhoogde hidrofobisiteit. Die siklometaalvormige rodium Cpxbiph-kompleks, wat die mees aktief is van die siklometaalvormige komplekse, wyk af van hierdie neiging. Die piridielkomplekse het lae sitotoksisiteit vir menslike embrionale nierselle (HEK) getoon in vergelyking met hul aktiwiteit teen P. falciparum-stamme, wat 'n aanduiding is van goeie selektiwiteit. Moontlike toekomstige werk behels die ondersoek van die potensiële werkingsmeganisme van hierdie komplekse en uitvoering van verdere in vitro-biologiese toetse op die siklometaal-komplekse, en die ligand kan moontlik verander word om die anti-malaria aktiwiteite van hierdie komplekse te verbeter. Alles in ag genome, is die nuutgesintetiseerde piridiel- en siklometaal organometaalkomplekse potensiële kandidate vir verdere ondersoek as moontlike anti-malaria middels.af_ZA
dc.description.versionMastersen_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/109410en_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch University, 2020en_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subjectChemistryen_ZA
dc.subjectMalariaen_ZA
dc.subjectAntimalarialen_ZA
dc.subjectAntiplasmodialen_ZA
dc.subjectMedicinal chemistryen_ZA
dc.subjectDrug discoveryen_ZA
dc.subjectOrganometallic complexesen_ZA
dc.subjectPlatinum group metalsen_ZA
dc.subjectOrganic chemistryen_ZA
dc.subjectInorganic chemistryen_ZA
dc.subjectUCTDen_ZA
dc.titleThe synthesis and evaluation of new organometallic benzimidazole Complexes as antiplasmodialsen_ZA
dc.typeThesisen_ZA
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