Design and synthesis of novel antimalarial agents

De Jager, Josephus Jacobus (2014-12)

Thesis (MSc)--Stellenbosch University, 2014.

Thesis

ENGLISH ABSTRACT: Malaria is a pestilent disease associated with massive socioeconomic burden of sub-Saharan Africa. This disease is caused by a blood infection of the single cellular parasite of the Plasmodium genus. Two enzymes of this parasite have been identified to be essential to the survival of this parasite, notably Spermidine Synthase and Protein Farnesyltransferase. The goal of this dissertation was to search for and synthesise novel inhibitors of these two enzymes with a strong focus towards understanding their structure/activity relationships. To achieve the first goal, molecular modelling was employed. An in-depth discussion is presented to describe the underlying principles relevant to this branch of computational chemistry. This ensures that the experiments using these methods are set-up correctly and results are interpreted within context. Two virtual high-throughput screens were then performed using prepared crystallographic structures of Spermidine Synthase. The first was pharmacophore based method and the second based on LibDock. The database used, containing 7.1 million compounds, was filtered using a custom developed tool prior to screening. Finally, CDOCKER was then used to investigate the activity of potential hit compounds. Spermidine Synthase has a natural affinity for adenosine and this trait was exploited by derivatising analogues to synthesise potential inhibitors of the enzyme. This was to be achieved by the incorporation of both electrophilic and nucleophilic moieties at selected positions, including the use of a high yielding Mitsunobu reaction. A number of additional residues were then synthesised and joined to the adenosine which were proposed to increase the active site occupancy and increase affinity to the enzyme. For the second enzyme targeted for inhibition, Protein Farnesyltransferase, indole was used as a starting scaffold to synthesise potential hits de novo. It was aimed to derivatise the indole at the Nʹ and 3ʹ positions. The crystal structure of one of the intermediates was published. Furthermore, a synthetic sequence which culminated in a palladium catalysed Suzuki coupling was performed.

AFRIKAANSE OPSOMMING: Malaria is ‘n peslike siekte wat geassosieer word met beduinde sosio-ekonomiese implikasies vir sub-Sahara Afrika. Die siekte word veroorsaak deur ‘n bloed infeksie van die enkel sellulêre parasiet van die Plasmodium genus. Twee ensieme, naamlik Spermidien Sintetase en Protein Farnesieltransferase, is geïdentifiseer om noodsaaklik te wees vir die oorlewing van die parasiet. Die doelwit van hierdie verhandeling is die soektog en sintese van oorspronklike inhibeerders van hierdie twee ensieme met ‘n sterk fokus daarop om struktuur/aktiwiteit interaksies te verstaan. Om die eerste doelwit te bereik is molekulêre modellering toegepas. ‘n Indiepte ondersoek word voorgestel om die onderliggende beginsels relevant tot hierdie tak van berekenkundige chemie te beskryf. Dit verseker dat eksperimente wat op hierdie tegnieke berus korrek opgestel word en dat die resultate binne konteks geïnterpreteer word. Twee virtuele hoë-deurset skerms was deurgevoer op voorbereide kristallografiese strukture van Spermidien Sintetase. Die eerste het berus op ‘n pharmakoforiese metode en die tweede op LibDock. ‘n Self-ontwikkelde sagteware gereedskap stuk is gebruik om a databasis van 7.1 miljoen verbindings te filtreer voor dit gebruik is in hoë-deurset skerms. Uiteindelik is CDOCKER gebruik om die potensiele aktiwiteit van “treffer” verbindings te beraam. Spermidien syntetase het ‘n natuurlike affiniteit vir adenosien en hierdie eienskap is benut deur analoeë af te lei na potensiële inhibeerders teen die ensiem. Dit is bewerkstellig deur die insluiting van beide elektrofiliese asook nukleifielese funksionele groepe op gekose posisies. Dit het die gebruik van ‘n hoë opbrengs Mitsunobu reaksie ingesluit. ‘n Aantal ander addisionele residueë is toe gesintetiseer en geheg aan die afgeleide adenosien om die ensiem setel te vul en sodoende die affinitieit te verhoog. Vir die tweede ensiem wat geteiken is vir inhibisie, Protein Farnesieltransferase, is indool benuttig as ‘n begin steier te dien om potensiële treffers de novo te sintetiseer. Dit is geteiken om die indool af te lei op die Nʹ en 3ʹ posisies en die kristal struktuur van een van hierdie tussengangers is gepubliseer. Verder is ‘n sintetiese weg, wat uitgeloop het op ‘n palladium gekataliseerde Suzuki koppeling, uitgevoer.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/96071
This item appears in the following collections: