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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/35469
Title: Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): Cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities
Authors: 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
Céline Freymond
Aritsara Jaruwat
Chatchadaporn Pinthong
Pinpunya Riangrungroj
Mouhssin Oufir
Matthias Hamburger
Pascal Mäser
Laura M. Sanz-Alonso
Susan Charman
Sergio Wittlin
Yongyuth Yuthavong
Pimchai Chaiyen
François Diederich
BASF SE
Swiss Tropical and Public Health Institute (Swiss TPH)
Universitat Basel
ETH Zurich
Thailand National Center for Genetic Engineering and Biotechnology
California Institute for Biomedical Research
Mahidol University
GlaxoSmithKline plc, Spain
Monash Institute of Pharmaceutical Sciences
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 9-Apr-2015
Citation: Journal of Medicinal Chemistry. Vol.58, No.7 (2015), 3117-3130
Abstract: © 2015 American Chemical Society. 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.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84927603340&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/35469
ISSN: 15204804
00222623
Appears in Collections:Scopus 2011-2015

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