Two sets of tricyclic 1,2,4-trioxanes containing the ABC (10, 11) and ACD ring portions (21, 22, 32, 33, 37, and 38) of artemisinin (1) were synthesized by successive photo-oxygenation of appropriate enol-ether precursors to 1,2-dioxanes and inter-and intramolecular reaction with a carbonyl compound or 0x0-substituted side-chain. The structures of 10, 21, and 22 were determined by X-ray analysis. The anti-malarial activity of all trioxanes, except 37 and 38, was evaluated in oitro against chloroquine-sensitive and chloroquine-resistant Piusmodium ,falcipurum parasites. Trioxanes 11 and 21 were as active as artemisinin (1). It was found that neither the lactone function nor rings Band D of 1 were essential for activity. A possible pharmacophore for artemisinin-like activity, which embodies a spirocyclopentane group attached to C(3) of 1,2,4-trioxane, was proposed.
Introduction.
-The worldwide spread of the resistance of Plasmodium falciparum to existing antimalarial agents together with the incidence of cross-resistance to structurally related derivatives makes the search for new drugs a matter of high priority [l]. The discovery that a naturally occurring sesquiterpenic 1,2,4-trioxane, artemisinin (l), is endowed with potent antimalarial properties has provided a providential lead for the development of improved versatile analogues [2]. However, this opportunity has not been exploited so far. Instead, derivatives of 1, namely arteether (2), artemether (3), sodium artesunate (4), and sodium artelinate (5) were chosen for clinical trials, despite difficulties in administration arising from poor solubility and stability [3] [4]. It occurred to us that the first step in designing better drugs based on 1 was to determine which parts of the skeleton were essential for the high activity characteristic of the parent structure. It is 0 0 Me M e 1 2 R = E t 3 R = M e 4 R = NaO,C(CH,),C(O) 5 R = 4-NaO,C-C8H,CH, Me 6 ') For the sake of clarity, raceniic mixtures are represented as single enantiomers in Schemes 2 7 .