| dc.description.abstract | Malaria is an infectious disease caused by Plasmodium parasites, with P. falciparum, responsible for most cases of morbidity and mortality. In 2014, malaria killed 438 000 people, with most deaths occurring in sub-Saharan Africa. The emergence and spread of P. falciparum drug resistance drives the search for new drugs to combat the disease.
Currently, artemisinins remain the mainstay of antimalarial chemotherapy. They possess superior potency, rapid action, good tolerability as well as a broad spectrum of antiplasmodial activity against P. falciparum. Undesirably, the use of these drugs is impeded by chemical and thermal instabilities as well as human neurotoxicity at high doses. Additionally, artemisinins have short pharmacological half-lives which result in recrudescence when used in monotherapy and ultimately the development of parasite resistance. Consequently, the WHO recommends ACT (artemisinin combination therapy) which is the administration of an artemisinin drug in partnership with a longer acting drug from a different antimalarial class, in order to elicit efficient and curative antimalarial treatment while also avoiding parasite resistance to artemisinins. Despite this strategy, the emergence of P. falciparum resistance has been reported. Attempts to combat artemisinin resistance and the search for new drugs are, therefore, incumbent.
Most shortcomings of clinical artemisinins are due to the structural lability of the hemiacetal D-ring. During this study, an investigation of robust and stable non-hemiacetal esters of artemisinin was conducted. The purpose was to find derivatives that would trade on the benefits of the clinically used artesunate (ARS), but offer more stability, improved solubility and most importantly, the inability to metabolise into dihydroartemisinin (DHA) both in vitro and in vivo.
In this study, truncated non-hemiacetal artemisinin ester derivatives were synthesised through the reaction of acid anhydrides, or acid chlorides with an artemisinin derived alcohol. Their structures were confirmed by NMR, IR and MS. The truncated esters were screened for in vitro antimalarial activity alongside chloroquine (CQ), DHA, ARM (artemether) and ARS against CQ sensitive (NF54) and CQ resistant (Dd2) strains of P. falciparum. Furthermore, the compounds were screened in vitro for cytotoxicity using mammalian WI-38 (human) and CHO (animal) cell lines. In vitro anticancer activity of the compounds was tested in TK10 (renal), UACC62 (melanoma) and MCF7 (breast) cancer cells. The compounds generally displayed poor anticancer activity therefore none of the compounds stood out as a potential anticancer candidate drug.
All synthesised esters were active against both strains of P. falciparum. The majority of the compounds were equipotent to ARS, with the exception of p-nitrobenzoate and furan-2-carboxylate, which had superior antimalarial activity against the resistant Dd2 parasites, however none showed superior activity to DHA. The derivatives had good safety profiles. Additionally, resistance index (RI<1) suggested that Dd2 parasites posed no resistance to the majority of the new derivatives. Most of the esters were found to be more stable than the clinical artemisinins. Ultimately, the p-nitrobenzoate 11 was identified as the best candidate for further investigation as a potential drug in the search for new, safe and effective antimalarial drugs, based on its efficacy, tolerability, safety profile, as well as thermal stability | en_US |
