Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities

Matthias C Witschel, Matthias Rottmann, Anatol Schwab, Ubolsree Leartsakulpanich, Penchit Chitnumsub, Michael Seet, Sandro Tonazzi, Geoffrey Schwertz, Frank Stelzer, Thomas Mietzner, Case McNamara, Frank Thater, Celine Freymond, Aritsara Jaruwat, Chatchadaporn Pinthong, Pinpunya Riangrungroj, Mouhssin Oufir, Matthias Hamburger, Pascal Maser, Laura M Sanz-AlonsoSusan Charman, Sergio Wittlin, Yongyuth Yuthavong, Pimchai Chaiyen, Francois Diederich

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37 Citations (Scopus)


Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 Å resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model.
Original languageEnglish
Pages (from-to)3117-3130
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number7
Publication statusPublished - 2015

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