Synthesis and antimalarial activity of amine derivatives of artemisinin
Cloete, Theunis Theodorus
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Malaria has since antiquity been a leading cause of morbidity and mortality throughout the world having serious health, sociological and financial implications. Today, the parasite kills an approximate 655 000 people annually, with most deaths being amongst pregnant women and children under the age of 5 in Africa. Plasmodium falciparum is the species that accounts for 91% of all case fatalities and predominates in Africa and Asia. The parasite is aggressive in its means of acquiring resistance, nullifying the majority of drugs used against it. Artemisinin, a sesquiterpene lactone with a peroxide bridge, was discovered in 1971 and was found to possess remarkable antimalarial activity. Together with its semi synthetic derivatives, artemisinin not only lack cross-resistance with other antimalarials but also has the remarkable ability to induce a 10 000 fold reduction in parasitemia. The artemisinin class of compounds is currently the basis of treatment favoured by the World Health Organisation (WHO) for the treatment of uncomplicated P. falciparum infection. Regrettably, resistance has started to emerge even against this class of compounds, characterised by a significantly longer in vivo parasite clearance time. The global impact of this disease and its ability to circumvent most efforts to counter it justifies the search for new treatment methods and drugs. The aim of this study was to synthesise three series of artemisinin-amine derivatives, to evaluate their antimalarial activity against both sensitive and resistant strains of P. falciparum and to determine their toxicity against mammalian cells. This may lead to new compounds with favourable properties and increased activity which can be used in the fight against malaria. Chapter 3 describes the synthesis of eleven 10-aminoethylether derivatives of artemisinin, confirmation of their structures by physical means and the determination of their in vitro antimalarial activity against the chloroquine sensitive (D10) and resistant (Dd2) strains of P. falciparum as well as their toxicity against Chinese hamster ovarian (CHO) cells. All derivatives were active against both strains of the parasite, with no mentionable toxicity. The highest activity was displayed by compound 8, a short chain aromatic derivative containing only one nitrogen atom, which was found to have comparable activity to artesunate (AS). Long chain polyamine derivatives had the lowest activity against both strains. An interesting correlation between the IC50, pKa values and resistance index (RI) was found. Chapter 4 compares the same 10-aminoethylether derivatives of artemisinin discussed in chapter 3 with eight 10-n-alkyl/aryl/aroyl ester derivatives previously synthesised in our group. The in vitro antimalarial activity of these nineteen compounds was determined against both the chloroquine sensitive (3D7) and resistant (K1) strains of P. falciparum, whilst their cytotoxicity was determined against both human embryonic kidney cells (HEK 293) and hepatocellular carcinoma cells (Hep G2). Both series of compounds showed activity versus the 3D7 and K1 strains, with the majority of compounds possessing potency either comparable with or higher than that of AS. None of the synthesised derivatives had any mentionable toxicity against the mammalian cells. The 10a-n-propyl and 10a-benzyl ester derivatives, 11 and 18 respectively, were the most active compounds against both strains, whilst the other ester derivatives also showed a slightly higher degree of activity than the aminoethers. Compound 29, featuring an isobutylamine substituent, was the most active of all aminoethers. Chapter 5 entails the synthesis of seven artemisinin-triazine hybrids, confirmation of their structures and the determination of their in vitro antimalarial activity against the 3D7 and K1 strains of P. falciparum, whilst their cytotoxicity was determined against HEK 293, Hep G2, B-lymphocyte cells (Raji) and human fibroblast cells (BJ). The synthesised hybrids all showed activity against both strains and were found to be non-toxic to all mammalian cells. Compound 17, featuring p-anisidine and 2-(diisopropylamino)ethylamine substituents on the triazine ring, was the most active of all synthesised compounds and had comparable activity to that of AS and artemether (AM), while being significantly more potent than chloroquine (CQ). Chapter 6 describes the synthesis and structure determination of six dimeric artemisinin triazine hybrids and the determination of their antimalarial activity and toxicity against the same strains of P. falciparum and mammalian cells as in chapter 5. All dimers showed activity against both strains and no noticeable toxicity towards any of the mammalian cell lines used. All synthesised compounds showed higher activity than CQ, irrespective of the P. falciparum strain considered. Compound 15, featuring aniline and morpholine substituents on the triazine ring, was not only meaningfully more potent than CQ but was also found to possess activity comparable to those of AS and AM against both malaria strains. Compounds 10, 11, 12 and 13 all had corresponding monomer equivalents as have been reported in chapter 5. Against both strains of P. falciparum, most dimer compounds were slightly more active than their monomer counterparts. This study delivered a number of compounds that exhibited activity comparable to that of potent antimalarial drugs currently on the market, and showed that there is ample scope for developments in the chemotherapy of malaria. These compounds stand as good candidates for in vivo and pharmacokinetic studies and may serve as leads for further investigations.
- Health Sciences