1.2.4- Trioxolanes antimalarials

The large diversity of biological activities including antimalarial, antioxoplasmosis, antileishmaniasis, antishistosomiasis, antitrypanosomiasis, antiviral, antifugal and even anticancer activities displayed by artemisinin and artemisinin derivatives (cf. Ref. 55 for a review) added to the multitude of artemisinin-inspired trioxanes, trioxolanes, tetraoxa-cycloalkanes and peroxide, homodimeric-, trimeric- and even tetrameric artemisinin derivatives recently designed and synthesized is a clear indication that in the future, these compounds will become even more important in the chemotherapy of various diseases, perhaps even above and beyond those mentioned here. 

Vennerstrom JL, Arbe-Bames S, Brun R, Charman SA, Chiu FCK, ChoUet J, Dong Y Dom A, Hunziker D, Matile H, McIntosh K, Padmanilayam M, Tomas JS, Scheurer C, Scomeaux B, Tang Y, Urwyler H, WittUn S, Charman WN. (2004) Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430 900-904. 

Tang Y, Dong Y, WittUn S, Charman S A, ChoUet J, Chiu FCK, Charman WN, Matile H, Urwyler H, Dom A, Bajpai S, Wang X, Padmanilayam M, Karle JM, Brun R, Vennerstrom JL. (2007) Weak base dispiro-l,2,4-trioxolanes Potent antimalarial ozonides. Bioorg Med Chem Lett 17 1260-1265. 

Vennerstrom JL, Arbe-Barnes S, Brim R, etal.. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430 900—904, 2004. 

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). 

The selective synthesis of substituted 1,2,4-trioxolanes has drawn considerable interest following indications that this heterocycle confers potent pharmacologic activity such as in the antimalarial area. 

In the decade since the publication of CHEC-II(1996) <1996CHEC-II(4)581>, two outstanding developments have taken place in the field of 1,2,4-trioxolanes (1) isolation of many stable 1,2,4-trioxolanes (secondary ozonides), and their facile synthesis by alternative methods to ozonation (2) most significantly, technological advances in the industrial synthesis of 1,2,4-trioxolanes by co-ozonolysis for preparing on an industrial scale the first fully synthetic antimalarial medicines. Earlier work has been excellently summarized <1984CHEC(6)851>. 

The laboratory of the authors has synthesized analogs related to artemisinin (133). Recently, an antimalarial synthetic trioxolane drug development candidate called OZ-277 (N5, also known as RBxlll60) (134) has sparked great interest and has progressed to Phase II clinical trials in India, Thailand, and... 

Dong Y, Tang Y, Chollet J, Matile H, Wittlin S, Charman SA, Charman WN, Tomas JS, Scheurer C, Snyder C, Scorneaux B, Bajpai S, Alexander SA, Wang X, Padmanilayam M, Cheruku SR, Brun R, Vennerstrom JL. Effect of functional group polarity on the antimalarial activity of spiro and dispiro-l,2,4-trioxolanes. Bioorg. Med. Chem. 2006 14 6368-6382. 

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