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

Witschel, Matthias C. and Rottmann, Matthias and Schwab, Anatol and Leartsakulpanich, Ubolsree and Chitnumsub, Penchit and Seet, Michael and Tonazzi, Sandro and Schwertz, Geoffrey and Stelzer, Frank and Mietzner, Thomas and McNamara, Case and Thater, Frank and Freymond, Céline and Jaruwat, Aritsara and Pinthong, Chatchadaporn and Riangrungroj, Pinpunya and Oufir, Mouhssin and Hamburger, Matthias and Mäser, Pascal and Sanz-Alonso, Laura M. and Charman, Susan and Wittlin, Sergio and Yuthavong, Yongyuth and Chaiyen, Pimchai and Diederich, François. (2015) Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT) : co-crystal structures of pyrazolopyrans with potent blood-and liver-stage activities. Journal of Medicinal Chemistry, 58 (7). pp. 3117-3130.

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Official URL: http://edoc.unibas.ch/dok/A6381801

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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 A 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
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Biologie (Hamburger)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias and Mäser, Pascal and Wittlin, Sergio and Hamburger, Matthias and Oufir, Mouhssin
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:0022-2623
e-ISSN:1520-4804
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Nov 2017 08:16
Deposited On:05 Jun 2015 08:53

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