Browsing by Author "Clements, Monica Jade"

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    Investigating the formation of multicomponent crystals of antiplasmodial agents
    (Stellenbosch : Stellenbosch University, 2019-03) Clements, Monica Jade; Blackie, Margaret A. L.; Le Roex, Tanya; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: The aim of this project was to explore the formation of multicomponent crystals of some known, as well as some novel, antiplasmodial agents and investigate and compare structures and properties of the antiplasmodials and the multicomponent crystals that they form. A series of five known 4-aminoquinoline antiplasmodial agents were chosen and the formation of multicomponent crystals with these compounds was investigated. The use of molecular electrostatic potential surfaces (MEPS) to calculate molecular complementarity with a specific coformer allowed us to rank a list of coformers according to the probability of forming multicomponent crystals with each 4- aminoquinoline. A total of nineteen multicomponent forms were obtained by liquid-assisted grinding, and these were characterised by PXRD, IR, TGA and DSC. Possible reasons are given for why two of the five 4-aminoquinolines yielded only amorphous multicomponent products, while three yielded crystalline products. Additionally, a brief discussion is given for the reasonably low success rate (38%) of the MEPS method for coformer selection. Attempts were then made to synthesise a series of novel aminoferrocene-containing lapatinib analogues so that the abovementioned knowledge could be applied to a novel system. While, we successfully achieved the synthesis of the precursor fragments, the key reaction that coupled the aminoferrocene fragment to the lapatinib core – the Suzuki-Miyaura reaction – proved more challenging than expected. After substantial effort, the desired product was obtained (as detected by LC-MS), however it could not be isolated, most likely due to low yields. The use of an amine or amide linker (instead of a direct carbon-carbon bond) was also investigated, however these attempts were also unsuccessful. A series of 6-substituted quinazolin-4(3H)-ones, formed serendipitously during the synthesis of the lapatinib analogues, were also studied for their ability to form multicomponent crystals. The MEPS method to select coformers was applied and liquid-assisted grinding was used to form eight novel multicomponent crystals. Interestingly, only one of the quinazolinone derivatives formed multicomponent crystals with the chosen coformers, while the remaining three yielded only mixtures of starting materials. Possible explanations for this were explored and it is clear that there are additional factors that play a larger role than initially thought. This study shows that quinoline- and quinazolinone-based antiplasmodial agents warrant further attention for the formation of multicomponent crystals. The work described in this thesis provides a greater understanding of the ability of these molecules to form multicomponent crystals. Together with similar studies, this knowledge could be applied to related systems, which would one day allow for accurate predictions and the formation of multicomponent crystals of antiplasmodial agents with tailored properties.