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 bic

SUBMITTER: Kato N 

PROVIDER: S-EPMC5515376 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature