Recent Developments with 1,2,4-Trioxane-Type Artemisinin Analogues

Artemisinin, a highly oxygenated sesquiterpene lactone endoperoxide isolated by Chinese researchers in 1971 has been found to be a superior plasmocidal and blood schizontocidal agent to conventional antimalarial drugs against malarial strains. Since then, an enormous amount of work has been done on this molecule by different groups covering aspects such as characterisation, total synthesis, understanding of the mechanism of action through QSAR studies, etc. which has unveiled tremendous amount of information about this molecule and resulted in a large number of published and patented literature. These studies have enabled scientists during the nineties to delineate the basic structural requirement - the 1,2,4-trioxane ring system as the essential pharmacophore. Since then a large number of simpler molecules containing mainly the core pharmacophore have been synthesized and evaluated against different malaria strains; many of which have shown even better plasmocidal activity than the parent molecule. Recent studies have also generated information on toxicity of some of the initial derivatives, viz. arteether, artemether, etc. A lot of efforts have been made to produce structural changes viz. synthesis of C-10 carba-analogues, ring-contracted derivatives, fluoro derivatives, simple 1,2,4-trioxanes etc. These studies aim to produce derivatives having maximum potency and minimum toxicity.