A DFT study of free radicals formed from artemisinin and related compounds Michael G.B. Drew a, * , John Metcalfe a,1 , Fyaz M.D. Ismail b a School of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK b The Medicinal Chemistry Research Group, The School of Pharmacy and Chemistry, Liverpool John Moores University, Liverpool L3 3AF, UK Received 12 August 2004; revised 30 August 2004; accepted 31 August 2004 Available online 28 October 2004 Abstract Ab initio calculations using density functional theory have shown that the reactions that occur between artemisinin, 1, a cyclic trioxane active against malaria, and some metal ions and complexes lead to a series of radicals which are probably responsible for its therapeutic activity. In particular it has been shown that the interaction of Fe(II) with artemisinin causes the O–O bond to be broken as indeed does Fe(III) and Cu(I), while Zn(II) does not. Calculations were carried out with Fe(II) in several different forms including the bare ion, [Fe(H 2 O) 5 ] 2C and [FeP(Im)] (P, porphyrin; Im, imadazole) and similar results were obtained. The resulting oxygen-based radicals are readily converted to more stable carbon-based radicals and/or stable products. Similar radicals and products are also formed from two simple model trioxanes 2 and 3 that show little or no therapeutic action against malaria although some subtle differences were obtained. This suggests that the scaffold surrounding the pharmacophore may be involved in molecular recognition events allowing efficient uptake of this trioxane warhead into the parasite. q 2004 Elsevier B.V. All rights reserved. Keywords: Artemisinin; Malaria; Density functional theory; Iron; Trioxane rings 1. Introduction Artemisinin (1) is a powerful anti-malarial drug having significant activity against strains of the disease which are resistant to chloroquine. It is a natural product isolated from the Chinese herb Artemisia annua L. (Qinghao) and has the characteristics of high potency against the parasite whilst possessing low toxicity during treatment of vertebrate malaria infections [1]. The structure of this compound is rather unique among natural products in that it contains the very unusual 1,2,4-trioxane ring system [2,3]. It was sufficiently unusual that it was originally characterised as an ozonide until revised crystallographic analysis provided unambiguous structural elucidation. For a drug to be effective against a pathogen such as the malaria parasite, it must reach the site of action in sufficient concentration and then interact with these receptors before it is either deactivated and/or eliminated by either the host or the parasite. Extensive pharmacological and biochemical evaluation revealed that this compound was a blood schizonticide that is preferentially imported into malaria infected erythrocytes via the parasitophorous duct [4]. It has been also shown that artemisinin and related trioxanes demonstrate useful activity against selected carcinomas [5]. 2. Mode of action The mode of action of artemisinin has been suggested to involve at least two distinct steps [4,6–8]. The first step, cleavage of the endoperoxide bridge in the 1,2,4-trioxane ring, is thought to be catalysed by intraparasitic iron or heme which generates unstable, highly reactive, free radical 0166-1280/$ - see front matter q 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.theochem.2004.08.028 Journal of Molecular Structure (Theochem) 711 (2004) 95–105 www.elsevier.com/locate/theochem * Corresponding author. Tel.: C44 118 378 8789; fax: C44 118 378 6331. E-mail address: m.g.b.drew@reading.ac.uk (M.G.B. Drew). 1 On leave from IMI Institute for Research and Development, POB 10140, Haifa Bay 26111, Israel.