Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT): Cocrystal Structures of Pyrazolopyrans with Potent Blood- and Liver-Stage Activities
| Autor: | 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, Céline Freymond |
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| Rok vydání: | 2015 |
| Předmět: |
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 |
| Zdroj: | Journal of Medicinal Chemistry. 58:3117-3130 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm501987h |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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