Synthesis and anti–malarial activity of ethylene glycol oligomeric ethers of artemisinin

Abstract

Malaria continues to be a major serious health problem and public health threat, with over two billion people at risk of contracting this deadly disease. Malaria is endemic in 92 countries and more than one million deaths per year are attributed to malaria, the mortality in African children being the highest. Drug-resistance to classical and existing anti-malarial drugs is a challenging problem in malaria control in most parts of the world, contributing to the need of developing new compounds for malaria treatment. Artemisinin is a sesquiterpene lactone endoperoxide and the first natural 1,2,4-trioxane isolated from Artemisia annua. Artemisinin and its derivates are of special biological interest because of their outstanding anti-malarial activity against chloroquine-resistant P. falciparum and cerebral malaria. The reason for this is their unusual chemical structures and the difference in their mechanism of action compared to other anti-malarials. The endoperoxide bridge of artemisinin and a heme iron play critical roles in the mechanism of action of artemisinin. The reaction mechanism consists of two distinct steps, the first step an activation step and the second step an alkylation step. During the activation step, the heme iron breaks the endoperoxide linkage of artemisinin and an oxygen free radical is produced, which is subsequently rearranged to form a carbon-centered (C4) free radical. In the alkylation step, the carbon free radical alkylates specific malarial proteins, which causes a lethal damage to malarial parasites. However, the use of such endoperoxides is restricted by their poor oral bioavailability, poor solubility in oil and water, a short plasma half-life (30 minutes in plasma) and the high rate of recrudescent infections when used as monotherapy in short-course treatments, even though these drugs have a rapid onset of action and low reported toxicity. In order to overcome these pharmacokinetic deficiencies, a number of new analogues with improved efficacy and increased solubility were introduced, including oil-soluble artemether and arteether, but these compounds still have a short plasma half-life. Artemisinin, dihydroartemisinin, artemether and arteether are all poorly water-soluble compounds, which results in slower and incomplete absorption of these drugs into the systemic circulation. Therefore, it may be worthwhile to produce new artemisinin derivatives to hopefully develop a compound with enhanced pharmacokinetic properties resulting in better bioavailability and increased effectiveness. The aim of this study was to synthesise ethylene glycol oligomeric ethers of artemisinin, determine certain physicochemical properties and evaluate their anti-malarial activity compared to artemether and chloroquine. In this study eight ethylene glycol derivatives of artemisinin were synthesised by linkage of a polyethylene glycol chain of various chain lengths to C-10 of dihydroartemisinin. The structures of the prepared derivatives were confirmed by nuclear magnetic resonance spectroscopy (NMR) and mass spectroscopy (MS). The experimental aqueous solubility of the synthesised compounds increased with the decrease in the experimental partition coefficients, as the polyethylene glycol (PEG) chain length increased, validating both structure-aqueous solubility and structure-lipophilicity relationships within the series. The new ethylene glycol oligomeric ethers of artemisinin were tested in vitro against the chloroquine sensitive strain of Plasmodium falciparum (D-10). The results indicate that the anti-malarial activity increases with the elongating of the PEG chain length. The ethoxypoly (ethylene glycol) series (6a-8) showed higher anti-malarial activity than the methoxypoly (ethylene glycol) series (3-5b), thus showing that both hydrophilic and lipophilic properties are necessary for the enhancement of the anti-malarial activity. None of the synthesised compounds showed better anti-malarial efficacy than artemether. Compound (8), 2-[2-(2-ethoxyethoxy)ethoxy] ethoxy derivative, showed better anti-plasmodial activity than chloroquine and compounds (5a) and (6a) showed activity comparable to that of chloroquine. Compounds (3), (4), (5b), (6b) and (7) are less active than artemether and chloroquine. In all cases the anti-malarial activity of the β-isomers was higher than that of the α-isomers.