Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

Abstract

Antimalarial drugs have thus far been chiefly derived from two sources—natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

Genetic diversity of next generation antimalarial targets: A baseline for drug resistance surveillance programmes

“…Here we consider eleven gene-targets of key investigated compounds that due to their efficiency might become the next antimalarial drugs, and for which mutations conferring resistance have been identified in in vitro studies (Baragaña et al., 2015, Dong et al., 2011, Flannery et al., 2015, Herman et al., 2015, Kato et al., 2016, LaMonte et al., 2016, Lim et al., 2016, McNamara et al., 2013, Ross et al., 2014). These 11 genes were also selected because they are gene-targets for a range of new antimalarial compounds already under evaluation in clinical trials.…”

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

“…119–121). Among those, the eukaryotic elongation factor 2 (eEF2) and phenylalanine tRNA synthetase have been identified as targets of compounds active against all three parasite stages in humans 122,123 . With most of these targets, however, resistance has been flagged as a potential concern (Supplementary Table 2).…”

Antimalarial Potential of Carica papaya and Vernonia amygdalina in Mice Infected with Plasmodium berghei

“…Malaria remains one of the deadliest infectious diseases, caused by protozoan parasite of the genus Plasmodium [1]. Available therapeutic agents are already limited in their efficacy, while drug resistance threatens the ability to prevent and treat the infection [1].…”

“…Available therapeutic agents are already limited in their efficacy, while drug resistance threatens the ability to prevent and treat the infection [1]. Malaria is the leading cause of illness and death in sub-Saharan Africa with an annual mortality of approximately one million children under five [2].…”