Peroxides represent a new chemical class of antimalarial drugs (Figure 1). The first generation compounds are all derivatives of artemisinin, the active principle of a Chinese herbal remedy [1]. Artemisinin, or qinghaosu (green plant extract), is extracted from Artemesia annua, a plant which grows widely in South China. The first generation compounds currently in use are derivatives of the lactol, dihydroartemisinin, which is a major metabolite for each of the derivatives, and may be the most important chemical species for antimalarial activity in vivo. The promise of these compounds lies in their effectiveness against chloroquine-resistant parasites and their rapid action against malaria. Moreover, they have been used for the treatment of malaria in three million patients with few reports of clinically significant toxicity [2]. Figure 1 Chemical structures of ‘First’ and ‘Second’ generation peroxides. The fenozan, tetroxane and tricyclic trioxanes are totally synthetic compounds prepared from readily available starting materials. The first generation DHA ... The drawback with artemisinin and related compounds is that they suffer from poor bioavailability: the relative bioavailability of oral artemisinin (vs intramuscular) and intramuscular artemether (vs oral) and the bioavailability of artesunate are all within a range of 15–30% [3–5]. This may be one of the reasons for the relatively high rate of recrudescence associated with peroxide monotherapy. Their complex chemical structures are not essential for pharmacological activity and there has, therefore, been a drive to design and synthesize simpler endoperoxides which have greater in vivo potency. To date, more than 1000 new endoperoxides belonging to several chemical classes have been prepared. A number of ‘second generation’ peroxides have been developed, including arteflene (Figure 1). This is a synthetic peroxide developed from yingzhaosu A, the complex active constituent of the Chinese plant Artabotrys uncinatus, after it was shown to have antimalarial activity [6]. It has been tested in clinical trials in Africa. The ‘first generation’ artemisinin derivatives, as described above, are chemically simple esters and ethers of the parent lactol, dihydroartemisinin (Figure 1) [7, 8]. These compounds are generally more potent than artemisinin both in vitro and in vivo, and provide a wider choice of formulations which are more easily administered to patients in the field. Artemether and arteether are more oil soluble than artemisinin and are currently undergoing clinical trials under WHO sponsorship [8]. Other first generation derivatives include sodium artesunate, the DHA β-O-succinate half ester sodium salt, and sodium artelinate, the corresponding DHA β-O-p-carboxybenzyl ether sodium salt. Both of these compounds, which are water soluble, are currently under investigation as intravenous treatments for severe malarial infections [8]. Given the obvious pharmacokinetic limitations of the ‘first generation’ analogues and the realization that the peroxide bridge is the essential pharmacophore for biological activity, medicinal chemists have developed a range of second generation derivatives. Representative compounds include the bicyclic fenozan type derivatives, synthesized by Jefford et al. [9], the tetroxanes synthesized by Vennerstrom [10] and tricyclic simplified derivatives prepared by Posner and coworkers [11]. The discovery that several of the first generation artemisinin derivatives are metabolised extensively to DHA has prompted other workers to prepare C-10-carba deoxy derivatives (for a review see Meshnick et al. [1]). These compounds cannot be metabolised to DHA, which undergoes fairly rapid clearance [8], and should therefore have longer half-lives in vivo. The initial focus of the medicinal chemist is clearly directed towards the discovery of simpler (hence often less expensive) and more potent compounds, which provides not only lead compounds for therapeutic use, but also pharmacological tools to define the mechanism of action of this class of agent and the essential pharmacophore. A QSAR study of antimalarial activity indicates that docking between an active trioxane and the receptor, haem, could be the crucial step preliminary to drug action [12]. Drug safety is an important consideration which has to be evaluated in concert with efficacy at the earliest possible stage in drug development. It is therefore essential to define the potential hazards associated with second or third generation peroxides that present greater and more prolonged systemic exposure and design appropriate test systems for screening for drug toxicity. The specific questions which need to be addressed during further chemical development of peroxide antimalarials are as follows. Will such chemical modifications lead to loss of the high degree of selective therapeutic potency noted for first generation peroxide antimalarials? Will chemical modification result in greater exposure of mammalian systems to hazards posed by the peroxide group such as the neurotoxicity observed in rodents given first generation peroxides? The purpose of this review is to address each of these questions from chemical and clinical perspectives.
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Aug 1, 2024
Iryna Bryshten + 3
