Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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, KMJ; 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, A-M; Avery, VM; Bhatia, SN; Burke, JE; Catteruccia, F; Clardy, JC; Clemons, PA; Dechering, KJ; Duvall, JR; Foley, MA; Gusovsky, F; Kocken, CHM; Marti, M; Morningstar, ML; Munoz, B; Neafsey, DE; Sharma, A; Winzeler, EA; Wirth, DF; Scherer, CA; Schreiber, SL

Published Date

  • October 2016

Published In

Volume / Issue

  • 538 / 7625

Start / End Page

  • 344 - 349

PubMed ID

  • 27602946

Pubmed Central ID

  • PMC5515376

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature19804


  • eng