Synthesis, antimalarial activity and cytotoxicity of 10-aminoethylether derivatives of artemisinin Theunis T. Cloete a , J. Wilma Breytenbach b , Carmen de Kock c , Peter J. Smith c , Jaco C. Breytenbach a , David D. N’Da a,⇑ a Department of Pharmaceutical Chemistry, North-West University, Potchefstroom 2520, South Africa b Statistical Consultation Services, North-West University, Potchefstroom 2520, South Africa c Department of Pharmacology, University of Cape Town, Groote Schuur Hospital, Observatory 7925, South Africa article info Article history: Received 4 April 2012 Revised 29 May 2012 Accepted 5 June 2012 Available online 15 June 2012 Keywords: Artemisinin Plasmodium falciparum Microwave Malaria abstract In this study, a series of 11 10-aminoethylether derivatives of artemisinin were synthesised and their antimalarial activity against both the chloroquine sensitive (D10) and resistant (Dd2) strains of Plasmo- dium falciparum was determined. The compounds were prepared by introducing aliphatic, alicyclic and aromatic amine groups with linkers of various chain lengths through an ethyl ether bridge at C-10 of artemisinin using conventional and microwave assisted syntheses, and their structures were confirmed by NMR and HRMS. All derivatives proved to be active against both strains of the parasite. The highest overall activity was displayed by the short chain aromatic derivative 8 (IC 50 = 1.44 nM), containing only one nitrogen atom, while long chain polyamine derivatives were found to have the lowest activity against both strains. An interesting correlation between the IC 50 ,pK a values and resistance index (RI) was found. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Malaria is a protozoan infection transmitted to humans by the bite of an infected female anopheline mosquito. It is estimated that malaria kills about 655,000 people each year, 91% of whom are liv- ing in Africa and, most of them children under the age of 5 years. 1 An increase in resistance against most of the drugs currently used against malaria has led to the dramatic increase in the global death toll. Chloroquine (CQ) and other synthetic quinoline compounds has been the mainstay of malaria chemotherapy for five decades, but resistance against these and the antifolate anti- malarials have spread rapidly making these drugs obsolete in most of the areas afflicted by this disease. 2,3 The artemisinin class of compounds ( Fig. 1) are currently the ba- sis of treatment preferred by the World Health Organization. 4 Arte- misinin, a trioxane endoperoxide compound, is one of the most rapidly acting antimalarials with the broadest effective range but is however poorly soluble in both oil and water. In an effort to overcome this solubility problem, the first generation analogs of artemisinin, viz. artemether, arteether and sodium artesunate, were synthesised. Unfortunately these derivatives have relatively short elimination half-lives creating an elevated risk of high recru- descence rates. 5–7 In an effort to prevent the artemisinin class of compounds from suffering the same fate as the classic antimalarial drugs, they are mostly used in artemisinin-based combination therapies (ACTs) which entail combining a semi-synthetic artemisinin derivative with another drug of a different chemical class. These ACTs do not only compensate for artemisinin’s poor pharmacokinetic prop- erties, but also decrease the likelihood that resistance against this class would emerge. Despite these efforts, resistance against artesunate has already been reported at the Thai-Cambodian and Thai-Myanmar borders, where significantly prolonged in vivo par- asite clearance times have been observed. 8,9 This is a stark remin- der of the exceptional ability of the malaria parasite to acquire resistance against a huge variety of chemical compounds, and a realisation that the loss of this important drug class would have dire consequences for millions of people around the world. Polyamine compounds have been found to have implications in a great number of various processes in the malaria parasite. The natural occurring polyamines spermidine, putrescine and sperm- ine have an important function in the regulation of growth and differentiation in an array of cell types. 10 These polyamine compounds, existing as polycations in vivo, are taken up by the malaria parasite through a polyamine transport system that recog- nises specific point charges on these compounds and then actively transports them into the malarial cells. The rapidly growing malar- ia parasite needs a substantial amount of these polyamine com- pounds and is reliant on exogenous sources of polyamines together with the polyamine transport system to provide it with the necessary quantities. 11 Researchers have proposed that a moi- ety that has the capability of being recognised by the polyamine transport system could act as a vector when coupled to another 0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2012.06.014 ⇑ Corresponding author. Tel.: +27 18 299 2516; fax: +27 18 299 4243. E-mail address: david.nda@nwu.ac.za (D.D. N’Da). Bioorganic & Medicinal Chemistry 20 (2012) 4701–4709 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc