Investigating the formation of multicomponent crystals of antiplasmodial agents

Clements, Monica Jade (2019-03)

Thesis (PhD)--Stellenbosch University, 2019.

Thesis

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.

AFRIKAANSE OPSOMMING: Die doel van hierdie projek was om die vorming van multikomponent kristalle van sommige bekende sowel as sommige nuwe, antiplasmodiese middels te ondersoek en om die strukure en eienskappe van die antiplasmodiese en die multikomponentkristalle wat hulle vorm, te odersoek en vergelyk. 'n Reeks van vyf bekende 4-aminokwinolien-antiplasmodiese middels is gekies en die vorming van multikomponent kristalle met hierdie verbindings is ondersoek. Die gebruik van molekulêre elektrostatiese potensiaal oppervlaktes (MEPS) om molekulêre komplementariteit met 'n spesifieke kovormer te bereken, het ons toegelaat om 'n lys van kovormers te rangskik volgens hul waarskynlikheid om multikomponent kristalle met elke 4-aminokwinolien te vorm. In totaal in negentien multikomponent vorms verkry deur middel van vloiestof-vergemaklikde meganiese chemie, en is beskryf deur PXRD, IR, TGA en DSC. Moontlike redes word gegee waarom twee van die vyf 4- aminokwinolien molekules slegs amorfiese multikomponent produkte opgelewer het, terwyl drie kristallyne produkte opgelewer het. Daarbenewens word 'n kort bespreking gegee oor die redelike lae suksessyfer (38%) van die MEPS-metode vir die keuse van kovormers. Pogings is dan aangewend om 'n reeks nuwe aminoferroseen-bevattende lapatinib-analoë te sintetiseer sodat die bogenoemde kennis op 'n nuwe stelsel toegepas kan word. Ons het die sintese van die voorloperfragmente suksesvol voltooi, maar die sleutelreaksie wat die aminoferoseenfragment aan die lapatinib-kern koppel – die Suzuki-Miyaura-reaksie – was meer uitdagend as verwag. Na aansienlike moeite is die verlangde produk verkry (soos aangetoon deur LC-MS), maar dit kon nie geïsoleer word nie, waarskynlik as gevolg van lae opbrengste. Die gebruik van 'n amien- of amiedskakelaar (in plaas van 'n direkte koolstof-koolstofbinding) is ook ondersoek, maar hierdie pogings was ook onsuksesvol. ʼn Reeks 6-gesubstitueerde kwinazolinoon wat gevorm is tydens die sintese van die lapatinib analoge, is ook bestudeer vir hul vermoë om multikomponent kristalle te vorm. Die MEPS-metode om koformers te kies is toegepas en vloiestof-vergemaklikde meganies chemie is gebruik om agt nuwe multikomponent kristalle te vorm. Slegs een van die kwinazolinoon analoge multikomponent kristalle gevorm met die gekose koformers, terwyl die oorblywende drie slegs mengsels van die uitgangsmateriaal opgelewer het. Moontlike verduidelikings hiervoor is ondersoek en dit is duidelik data daar addisionele faktore is wat ʼn groter rol speel as aanvanklik gedink. Hierdie studie toon dat kwinolien- en kwinazolinoon-gebaseerde antiplasmodiese middels verdere aandag verdien rakende die vorming van multikomponent kristalle. Die werk wat in hierdie tesis beskryf word, bied 'n groter begrip oor die vermoë van hierdie molekules om multikomponent kristalle te vorm. Saam met soortgelyke studies kan hierdie kennis toegepas word op verwante stelsels, wat eendag kan toelaat vir akkurate voorspellings en die vorming van multikomponent kristalle met antiplasmodiese middels.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/105581
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