Dihydroartemisinin esters as prodrugs against resistant P. falciparum strains

Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2012.Malaria is caused by the Plasmodium sp. parasite that infects the red blood cells. Of the four types of malaria, the most serious type is transmitted by Plasmodium falciparum species. It can be life threatening. The other types of malaria (P. vivale, P. ovale and P. malariae) are generally less serious and are not life threatening. The existence of malaria as an enemy of humankind certainly predates written history. For thousands of years malaria has been a deadly scourge, and it remains one today. From American president John Adams who nearly succumbed to malaria in Amsterdam while on a diplomatic mission, back down to the timeline to the early Chinese, Indians, Greeks and Romans, malaria has not spared its victims, rich or poor. It wasn’t until the 19th Century that information about the true cause of malaria became known. Yet despite this knowledge, malaria still ravages Sub–Saharan Africa, South–East Asia and Latin America, taking as its victim’s mainly young children and pregnant women. However, without certain discoveries leading to a better understanding of malaria, new groundbreaking work wouldn’t be possible. Artemisinin and its derivatives are developing into a very important new class of antimalarial and their usage is becoming more common in the fight against malaria. The most commonly used and applied of these derivatives are artesunate, artemether, arteether and dihydroartemisinin. The discovery of artemisinin as the pharmacological active ingredient in an age old Chinese herb, Artemisia annua, was a major breakthrough in malaria chemotherapy. Discovery of qinghaosu in the 1970s sparked a new age for chemotherapy of malaria, and greatly inspired further research on organic peroxides. This generated widespread interest and led to the design and synthesis of organic peroxides into a highly active area of organic chemistry. The artemisinin derivatives act quickly and are eliminated quickly. Their rapid onset makes them especially effective against severe malaria. Their rapid disappearance may be a key reason why artemisinin resistance has been so slow to develop, and may be the reason why recrudences are so common when these drugs are used in monotherapy. Since their isolation, artemisinins have had a substantial impact on the treatment of malaria. Although very potent, the use of artemisinins as prophylactic antimalarials is not recommended. The aim of this study was to synthesise ester derivatives of artemisinin, determine certain physicochemical properties such as aqueous solubility and partition coefficient, and to evaluate their antimalarial activity in comparison to dihydroartemisinin and chloroquine. In this study eight esters of dihydroartemisinin (DHA) were synthesised by substitution at C– 10. The structures of the prepared derivatives were confirmed by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). The new artemisinin esters were tested in vitro against the chloroquine sensitive strain of Plasmodium falciparum (D10). All the compounds tested showed activity against the D10 strain. All of the esters showed potency significantly better than chloroquine, except the octyl and decyl esters which were less active. The reason for the low activity could be ascribed to the fact that these two esters are both water immiscible oils, leading to solubility problems. The ethyl, butyl, phenyl and p–nitrophenyl esters all had similar IC50 values making their activity similar. The lowest IC50 value was displayed by the butyl ester with a value of 3.2 x 10–3 µM. The poorest activity was recorded by the two oils, the octyl and decyl esters, with IC50 values of 38 x 10–3 µM and 90.2 x 10–3 µM respectively. All other compounds showed less antimalarial potency against the D10 strain compared with the other reference drug dihydroartemisinin, except the butyl ester. The butyl ester 12 displayed activity comparable to that of DHA (IC50; 3.2 x 10–3 µM versus 3.8 x 10–3 µM), and is thus worthwhile being further investigated in terms of pharmacokinetics in order to determine its half–life. Statistically it is impossible to make structure–activity relationship (SAR) deductions from the data received as the number of compounds in the series is too small. The butyl (12) (IC50 = 3.2 µM), 4–nitrobenzyl (16) (IC50 =15 µM), 2–(acetyloxy) acetyl (17) (IC50 = 8.6 µM), and 2–phenylacetyl (18) (IC50 = 12.4 µM) esters showed on a 0.05 level statistically significantly better activity against the chloroquine sensitive D10 strain of Plasmodium falciparum than chloroquine itself while the decyl ester (14) (IC50 = 90.2 µM) was statistically significantly less potent. The activity of the octyl (13) (IC50 = 38.0 µM) and benzyl (15) (IC50 = 25.7 µM) esters did not differ from that of chloroquine. In comparison to dihydroartemisinin the propyl (11) (IC50 = 24.1 µM), octyl (13) (IC50 = 38.0 µM), decyl (14) (IC50 = 90.0 µM), and benzyl (15) (IC50 = 25.7 µM) esters proved to be statistically significantly less potent than DHA while the activity of the butyl (12) (IC50 = 3.2 µM), 4–nitrobenzyl (16) (IC50 =15.3 µM), 2–(acetyloxy) acetyl (17) (IC50 = 8.6 µM), and 2–phenylacetyl (18) (IC50 = 12.4 µM) esters did not differ from that of DHA.Master