89, R = COCH2NHCOOC4H9 (0

92, R=COC6H4COOCH3(p)

99, R=CH2C6H5

mice infected with P. berghei; in addition, 106 was found to be 10-fold more active than 1 in killing immature P. falciparum gametocytes.

To study the molecular mechanisms of action (discussed later in chapter 13) of antimalarial trioxane analogues of 1 with ferrous ion, Posner et. al. (1994; 1995a; 1995b; 1996), have designed and synthesised a number of 3- and 4-substituted tricyclic 1,2,4-trioxanes and evaluated their antimalarial activities. Trioxanes 107 and 108 possessed comparable activity to that of 1.

Jefford et al. (1993), have synthesised bicyclic and tricyclic 1,2,4-trioxanes containing the ABC and ACD ring portions of 1. The ABC ring containing trioxane 109 and ACD ring containing derivative 110 were as active as 1 in vitro against chloro-quine-sensitive and chloroquine-resisitant P. falciparum strains.

Several tricyclic seco-artemisinins containing ABC (Avery et al., 1990), and ACD (Avery et al., 1990a; 1993; 1994) rings of 1 and tri- and tetracyclic carba-artemisinin analogues have also been reported. All the seco-analogues retain antimalarial activity and the most active analogue, (-)-5-nor-4, 5-seco-artemisinin, 111, was as active as 1 in vitro against the D-6 strain of P. falciparum.

Zouhiri et al. (1998) have prepared tricyclic artemisinin analogues bearing a C5a methyl group; these were devoid of antiplasmodial activity which is consistent with the hypothesis that tight binding between haem and the a- face of the artemisinin molecule is necessary for activity.

Among a series of sulfide and sulphone 1,2,4-trioxanes, the sulphones were found to have higher in vitro activities against malaria parasites but the most potent was three-fold less active than artemisinin (Posner et al., 1998a).

The preparation of a number of tetracyclic and trioxane dimers has also been reported and several of these compounds have potent in vitro antiplasmodial and cytotoxic properties (Posner et al., 1997).

On the basis of a proposed mechanistic understanding of the mode of action of artemisinin Posner et al. (1998) synthesised a series of (tricyclic) 3-aryl, 1,2,4-trioxanes. The most active were four 12/3-methoxy-3-aryltrioxanes (112-115). While the in vitro antiplasmodial activities were up to 3-fold less than that of artemisinin, two of the compounds (113, 114) were up to twice as potent as artemisinin when given orally to P. berghei infected mice. The 3-aryl substitution in these compounds was designed to promote the formation of cytotoxic high-valent iron-oxo species which are postulated to be formed following the reaction of artemisinin derivatives with haem in malaria infected red blood cells. Another mechanism-based strategy involved the synthesis of 4-(hydroxyalkyl)trioxanes which were designed to enhance the formation of C4 radicals

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