Deorphaning Pyrrolopyrazines as Potent Multi‐Target Antimalarial Agents1. Issue 27 (4th June 2014)

• Record Type: Journal Article
• Authors: Reker, Daniel; Seet, Michael; Pillong, Max; Koch, Christian P.; Schneider, Petra; Witschel, Matthias C.; Rottmann, Matthias; Freymond, Céline; Brun, Reto; Schweizer, Bernd; Illarionov, Boris; Bacher, Adelbert; Fischer, Markus; Diederich, François; Schneider, Gisbert
• Is Part Of: Angewandte Chemie international edition. Volume 53:Issue 27(2014)
• Page Start: 7079
• Page End: 7084
• Publication Date: 2014-06-04
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201311162
• Languages: English
• ISSNs: 1433-7851

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <italic>Plasmodium falciparum</italic> in human red blood cells, and <italic>Plasmodium berghei</italic> 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 <italic>P. falciparum</italic> 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.</p> </abstract>