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

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

  • J Med Chem. 2015 Apr 9;58(7):3117-30. doi: 10.1021/jm501987h.
Matthias C Witschel 1,  Matthias Rottmann 2 3,  Anatol Schwab 4,  Ubolsree Leartsakulpanich 5,  Penchit Chitnumsub 5,  Michael Seet 4,  Sandro Tonazzi 4,  Geoffrey Schwertz 4,  Frank Stelzer 1,  Thomas Mietzner 1,  Case McNamara 6,  Frank Thater 1,  Céline Freymond 2 3,  Aritsara Jaruwat 5,  Chatchadaporn Pinthong 7,  Pinpunya Riangrungroj 5,  Mouhssin Oufir 8,  Matthias Hamburger 8,  Pascal Mäser 2 3,  Laura M Sanz-Alonso 9,  Susan Charman 10,  Sergio Wittlin 2 3,  Yongyuth Yuthavong 5,  Pimchai Chaiyen 7,  François Diederich 4
Affiliations

Affiliations

  • 1 †BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany.
  • 2 ‡Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, 4051 Basel, Switzerland.
  • 3 §Universität Basel, Petersplatz 1, 4003 Basel, Switzerland.
  • 4 ∥Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
  • 5 ⊥National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Khlong Luang, Pathum Thani 12120, Thailand.
  • 6 #California Institute for Biomedical Research (Calibr), 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.
  • 7 ∞Department of Biochemistry and Center of Excellence in Protein Structure and Function, Faculty of Science, Mahidol University, 272 Rama VI Road, Bangkok 10400, Thailand.
  • 8 ×Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • 9 ¶Diseases of the Developing World (DDW), GlaxoSmithKline, C. Severo Ochoa, 2, 28760 Tres Cantos, Spain.
  • 10 ○Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia.
PMID: 25785478 DOI: 10.1021/jm501987h
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-129651
    99.79%, SHMT抑制剂
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