Natural endoperoxides as promising anti-leishmanials

The discovery of artemisinin, an endoperoxide, encouraged the scientific community to explore endoperoxides as potential anti-parasitic molecules. Although artemisinin derivatives are rapidly evolving as potent antimalarials, their potential as anti-leishmanials is emerging gradually. The treatment of leishmaniasis, a group of neglected tropical diseases is handicapped by lack of effective vaccines, drug toxicities and drug resistance. The weak antioxidant defense mechanism of the Leishmania parasite due to lack of catalase and a selenium dependent glutathione peroxidase system makes them vulnerable to oxidative stress, and this has been successful exploited by endoperoxides. The study aimed to review the available literature on the anti-leishmanial efficacy of natural endoperoxides with a view to achieve insights into their mode of action. We reviewed more around 110 research and review articles restricted to the English language, sourced from electronic bibliographic databases including PubMed, Google, Web of Science, Google scholar etc. Natural endoperoxides could potentially augment the anti-leishmanial drug library, with artemisinin and ascaridole emerging as potential anti-leishmanial agents. Due to higher reactivity of cyclic peroxide moiety, and exploiting the compromised antioxidant defense of Leishmania, endoperoxides like artemisinin and ascaridole potentiate their leishmanicidal efficacy by creating a redox imbalance. Furthermore, these molecules minimally impair oxidative phosphorylation, and instead inhibit glycolytic functions, culminating in depolarization of the mitochondrial membrane and depletion of ATP. Additionally, the carbon-centered free radicals generated from endoperoxides, participate in chain reactions that can generate even more reactive organic radicals that are toxic to macromolecules, including lipids, proteins and DNA, leading to cell cycle arrest and apoptosis of Leishmania parasites. However, the precise target(s) of the toxic free radicals remains open-ended. In this overview, the spectrum of natural endoperoxide molecules as major anti-leishmanials and their mechanism of action has been delineated. In view of the substantial evidence that natural endoperoxides (e.g. artemisinin, ascaridole) exert a noxious effect on different species of Leishmania, identification and characterization of other natural endoperoxides is a promising therapeutic option worthy of further pharmacological consideration.