Page - (000338) - in Biomedical Chemistry: Current Trends and Developments

The addition of the enamine group on the side-chain creates an almost time-release effect as it is hydrolyzed to release primaquine. This leads to an interesting hypothesis that perhaps while the same metabolites may well be responsible for efficacy and toxicity, efficacy could be exposure driven while toxicity is concentration dependent, providing an in-road to improvements in therapeutic index. Although in the author’s opinion, circumstantial evidence overwhelmingly points to an inextricable link between efficacy and toxicity in this class that may make it difficult, if not impossible, to support the large-scale development of a new candidate. 3.4.4.3 Artemisinins and other Endoperoxides Although sweet wormwood was used for over 2000 years in China to treat malaria, the active ingredient, artemisinin, was not identified until the 1970’s (Fig. 3.4.5) (Faurant, 2011). At present, several artemisinin compounds are clinically available for use including artemisinin, artesunate, dihydroartemisinin (DHA), and artemether. Other experimental drugs exist but are not clinically available. Due to poor tolerability and hence compliance with quinine, artemisinin compounds have drastically risen in popularity for the treatment of falciparum malaria (Shanks, 2006). Artemisinin resistance was first reported in Southeast Asia in 2008, and evidence suggests that it is spreading (Ashley, 2014; Dondorp, 2009; Thriemer, 2014). Widespread resistance to the most powerful new weapon in the fight against malaria could de- rail many ongoing efforts to eradicate the disease in the endemic world. As such, it is widely acknowledged that combination therapy should be the standard of care. The WHO currently recommends artemisinin combination therapy (ACT) consisting of DHApiperaquine, followed with a 0.75 mg kg-1 single dose of primaquine for the treatment of uncomplicated malaria (WHO, 2010). At present, research is still ongoing as to the exact killing mechanism for the functional endoperoxide bridge contained in the artemisinins, however, it is thought to be a result of membrane depolarization and subsequent interference with electron transport (Antoine, 2014). Further development of synthetic and semi-synthetic artemisinins is still