Publication: Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): Cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities
Issued Date
2015-04-09
Resource Type
ISSN
15204804
00222623
00222623
Other identifier(s)
2-s2.0-84927603340
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Medicinal Chemistry. Vol.58, No.7 (2015), 3117-3130
Suggested Citation
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 Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): Cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities. Journal of Medicinal Chemistry. Vol.58, No.7 (2015), 3117-3130. doi:10.1021/jm501987h Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/35469
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Title
Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): Cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities
Author(s)
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
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
Other Contributor(s)
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.