Abstract
Malaria is one of the leading causes of death worldwide and a major concern to children under five. This disease is caused by a parasite from the Plasmodium genus and transferred to human beings by a female Anopheles mosquito. The P. falciparum and P. vivax are reportedly the deadliest species among other Plasmodium species. The World Health Organization (WHO) reports more malaria-related cases and deaths every year, with the African region accounting for ~95% of these cases and deaths. Treatment for malaria has existed for a long period. However, the increased usage of monotherapy drugs has hampered the progress, conversely encouraging drug resistance from the parasite. Currently, using a combination of two or more drugs possessing different mode of action (MOA) as a mimic of natural plant extracts is the recommended treatment of malaria by the WHO. Moreover, Artemisinin-based Combination Therapy (ACT), being the last line of defence in treating malaria coupled with reports of artemisinin-resistant strains of P. falciparum in South-East Asia, raise notable concerns. As such, there is a need to enlarge the scope of chemotypes with potential antiplasmodial activity by screening rationally designed compounds. Our group has already reported the successful incorporation of the sulfone and sulfoximine moieties to carbohydrate-derived thiochromans and established their antiplasmodial properties with encouraging IC50 values against both chloroquine-sensitive (3D7) and chloroquine-resistant (FCR3) strains. Isoxazole-bearing compounds have also been reported to possess biological and antiplasmodial activities. Therefore, it was anticipated that the synthesis of hybrid compounds containing the sulfoximine and isoxazole moieties would yield novel chemotypes with improved antiplasmodial potency. A series of alkyl aryl sulfoximines 96a-t were synthesized from their relative alkyl aryl sulfides 97 through simultaneous one-pot NH- and O-transfer using readily available nitrogen source oxidising agent in an open-air reaction. Concurrently, a series of 3,5-isoxazole derivatives 95a-c (containing bromomethyl at position 5) were synthesized through an in situ oxidation of benzaldoxime group into a nitrile oxide, further undergoing a rapid 1,3-dipolar cycloaddition in the presence of a π-system of a dipolarophile. This was followed by an SN2 reaction to successfully combine the two coupling partners to yield sulfoximine-isoxazole hybrids 94a-s in low to high yields. Furthermore, a bromination of the isoxazole ring of hybrid 94a, followed by a cross-coupling reaction, was adopted to expand the scope of the hybrids. These hybrid compounds were then iv | P a g e investigated for their antiplasmodial activity against the wild-type drug-sensitive strain (NF54) and multidrug-resistant strain (K1). The test results showed no significant activity for the most part against the parasite for the tested concentration range. Only six (6) of the tested hybrid compounds showed activity against the malaria parasite. However, the activity of these hybrids relative to standard antimalarial compounds was found to be very low. The replacement of short alkyl chains with medium or long alkyl chains on the sulfur atom positively affected the antiplasmodial potency of the hybrid. The alterations to aryl groups on both coupling partners had little impact on reducing the IC50 value with only p-tolyl (94e), p-anisyl (94o), or p-X (X=Br/Cl) substituted aryl group (94j/94r) showing potential to reduce the IC50 values. The overall results suggest that with a thorough investigation, these hybrid compounds could provide potential antiplasmodial agents.
M.Sc. (Chemistry)