1. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.
- Author
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Kato N, Comer E, Sakata-Kato T, Sharma A, Sharma M, Maetani M, Bastien J, Brancucci NM, Bittker JA, Corey V, Clarke D, Derbyshire ER, Dornan GL, Duffy S, Eckley S, Itoe MA, Koolen KM, Lewis TA, Lui PS, Lukens AK, Lund E, March S, Meibalan E, Meier BC, McPhail JA, Mitasev B, Moss EL, Sayes M, Van Gessel Y, Wawer MJ, Yoshinaga T, Zeeman AM, Avery VM, Bhatia SN, Burke JE, Catteruccia F, Clardy JC, Clemons PA, Dechering KJ, Duvall JR, Foley MA, Gusovsky F, Kocken CH, Marti M, Morningstar ML, Munoz B, Neafsey DE, Sharma A, Winzeler EA, Wirth DF, Scherer CA, and Schreiber SL
- Subjects
- Animals, Antimalarials administration & dosage, Antimalarials therapeutic use, Azabicyclo Compounds administration & dosage, Azabicyclo Compounds chemical synthesis, Azabicyclo Compounds pharmacology, Azabicyclo Compounds therapeutic use, Azetidines administration & dosage, Azetidines adverse effects, Azetidines pharmacology, Cytosol enzymology, Disease Models, Animal, Female, Liver drug effects, Liver parasitology, Macaca mulatta parasitology, Malaria, Falciparum prevention & control, Malaria, Falciparum transmission, Male, Mice, Phenylalanine-tRNA Ligase antagonists & inhibitors, Phenylurea Compounds administration & dosage, Phenylurea Compounds chemical synthesis, Phenylurea Compounds pharmacology, Phenylurea Compounds therapeutic use, Plasmodium falciparum cytology, Plasmodium falciparum enzymology, Safety, Antimalarials chemical synthesis, Antimalarials pharmacology, Azetidines therapeutic use, Drug Discovery, Life Cycle Stages drug effects, Malaria, Falciparum drug therapy, Plasmodium falciparum drug effects, Plasmodium falciparum growth & development
- 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.
- Published
- 2016
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