Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents.

TitleDeorphaning pyrrolopyrazines as potent multi-target antimalarial agents.
Publication TypeJournal Article
Year of Publication2014
AuthorsD Reker, M Seet, M Pillong, CP Koch, P Schneider, MC Witschel, M Rottmann, C Freymond, R Brun, B Schweizer, B Illarionov, A Bacher, M Fischer, F Diederich, and G Schneider
JournalAngewandte Chemie International Edition
Volume53
Start Page7079
Issue27
Pagination7079 - 7084
Date Published07/2014
Abstract

The discovery of pyrrolopyrazines as potent antimalarial agents is presented, with the most effective compounds exhibiting EC50 values in the low nanomolar range against asexual blood stages of Plasmodium falciparum in human red blood cells, and Plasmodium berghei liver schizonts, with negligible HepG2 cytotoxicity. Their potential mode of action is uncovered by predicting macromolecular targets through avant-garde computer modeling. The consensus prediction method suggested a functional resemblance between ligand binding sites in non-homologous target proteins, linking the observed parasite elimination to IspD, an enzyme from the non-mevalonate pathway of isoprenoid biosynthesis, and multi-kinase inhibition. Further computational analysis suggested essential P. falciparum kinases as likely targets of our lead compound. The results obtained validate our methodology for ligand- and structure-based target prediction, expand the bioinformatics toolbox for proteome mining, and provide unique access to deciphering polypharmacological effects of bioactive chemical agents.

DOI10.1002/anie.201311162
Short TitleAngewandte Chemie International Edition