1. Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT): Cocrystal Structures of Pyrazolopyrans with Potent Blood- and Liver-Stage Activities
- Author
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Thomas Mietzner, Sandro Tonazzi, Ubolsree Leartsakulpanich, Penchit Chitnumsub, Pimchai Chaiyen, Frank Thater, Sergio Wittlin, Susan A. Charman, Case W. McNamara, Michael Seet, Matthias Witschel, Matthias Hamburger, Anatol Schwab, Aritsara Jaruwat, Pascal Mäser, Mouhssin Oufir, Yongyuth Yuthavong, François Diederich, Chatchadaporn Pinthong, Frank Stelzer, Geoffrey Schwertz, Laura M. Sanz-Alonso, Pinpunya Riangrungroj, Matthias Rottmann, and Céline Freymond
- Subjects
Plasmodium berghei ,Plasmodium falciparum ,Plasmodium vivax ,Drug Evaluation, Preclinical ,Drug Resistance ,Administration, Oral ,Mice, Inbred Strains ,Chemistry Techniques, Synthetic ,Mice, SCID ,Pharmacology ,Crystallography, X-Ray ,Antimalarials ,In vivo ,parasitic diseases ,Drug Discovery ,Animals ,Humans ,Enzyme Inhibitors ,Malaria, Falciparum ,IC50 ,Glycine Hydroxymethyltransferase ,chemistry.chemical_classification ,Organisms, Genetically Modified ,biology ,Hep G2 Cells ,biology.organism_classification ,Rats ,Enzyme ,Liver ,chemistry ,Biochemistry ,Serine hydroxymethyltransferase ,Microsomes, Liver ,Microsome ,Pyrazoles ,Molecular Medicine ,Female - Abstract
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.
- Published
- 2015
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