Antimalarial endoperoxides synthetic

As described in this chapter, significant progress has been made in the elucidation of the chemical mechanisms of bioactivation and identification of potential biological targets of the antimalarial endoperoxide class of drug. Equally, medicinal chemists have had success in the preparation of both semi-synthetic artemisinin analogues and simplified... 

Erratic availability and high costs of the natural compound make further investigations for cheaper natural or synthetic endoperoxide-based antimalarials necessary. Meanwhile, a Belgian company, Dafra Pharma, Turnhout, is bringing the natural product and its derivatives onto the market [44]. 

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

Table 1 summarizes the synthetic and antimalarial profiles of selected endoperoxides. Clearly, synthetic organic chemistry has enabled several excellent potential drng candidates to be prepared, some of which have outstanding antimalarial properties. At the forefront of these efforts are the trioxolanes prepared by Vennerstrom and colleagnes. The challenge in this field in future years will be to construct additional endoperoxide templates that can be prepared in a few steps using scalable synthesis and have similar pharmacological profiles to lead semi-synthetic artemisinins and trioxolanes (e.g. 6). 

TABLE 1. Lead synthetic endoperoxide antimalarials (The table compares the antimalarial activities, the method of synthesis and the number of synthetic steps required for dmg synthesis)... 

Biomimetic Fe(ii) chemistry and synthetic studies on antimalarial and antitumour endoperoxides... 

J.P. Begue, D. Bonnet-Delpon, The future of antimalarials Artemisinins and synthetic endoperoxides, Drugs Fut. 30 (2005) 509-518. 

VII. ANTI MALARIAL ACTIVITIES OF SYNTHETIC ENDOPEROXIDE ANTIMALARIALS... 

Stocks, P.A. et al. (2007) Evidence for a common non-heme chelatable-iron-dependent activation mechanism for semisymthetic and synthetic endoperoxide antimalarial drugs. Angew. Chem. 46, 6278-6283... 

O Neill PM (2005) The therapeutic potential of semi-synthetic artemisinin and synthetic endoperoxide antimalarial agents. Expert Opin Investig Drugs 14 1117-1128... 

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