title: Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities.
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.
authors.affiliation: †BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany.
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Witschel
authors.affiliation: ‡Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, 4051 Basel, Switzerland.|§Universität Basel, Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.affiliation: ∥Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
authors.forename: Anatol
authors.initials: A
authors.lastname: Schwab
authors.affiliation: ⊥National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Khlong Luang, Pathum Thani 12120, Thailand.
authors.forename: Ubolsree
authors.initials: U
authors.lastname: Leartsakulpanich
authors.affiliation: ⊥National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Khlong Luang, Pathum Thani 12120, Thailand.
authors.forename: Penchit
authors.initials: P
authors.lastname: Chitnumsub
authors.affiliation: ∥Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Seet
authors.affiliation: ∥Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
authors.forename: Sandro
authors.initials: S
authors.lastname: Tonazzi
authors.affiliation: ∥Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Schwertz
authors.affiliation: †BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Stelzer
authors.affiliation: †BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mietzner
authors.affiliation: #California Institute for Biomedical Research (Calibr), 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.
authors.forename: Case
authors.initials: C
authors.lastname: McNamara
authors.affiliation: †BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Thater
authors.affiliation: ‡Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, 4051 Basel, Switzerland.|§Universität Basel, Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Freymond
authors.affiliation: ⊥National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Khlong Luang, Pathum Thani 12120, Thailand.
authors.forename: Aritsara
authors.initials: A
authors.lastname: Jaruwat
authors.affiliation: ∞Department of Biochemistry and Center of Excellence in Protein Structure and Function, Faculty of Science, Mahidol University, 272 Rama VI Road, Bangkok 10400, Thailand.
authors.forename: Chatchadaporn
authors.initials: C
authors.lastname: Pinthong
authors.affiliation: ⊥National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Khlong Luang, Pathum Thani 12120, Thailand.
authors.forename: Pinpunya
authors.initials: P
authors.lastname: Riangrungroj
authors.affiliation: ×Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Mouhssin
authors.initials: M
authors.lastname: Oufir
authors.affiliation: ×Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamburger
authors.affiliation: ‡Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, 4051 Basel, Switzerland.|§Universität Basel, Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Mäser
authors.affiliation: ¶Diseases of the Developing World (DDW), GlaxoSmithKline, C. Severo Ochoa, 2, 28760 Tres Cantos, Spain.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanz-Alonso
authors.affiliation: ○Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Charman
authors.affiliation: ‡Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, 4051 Basel, Switzerland.|§Universität Basel, Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: ⊥National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Khlong Luang, Pathum Thani 12120, Thailand.
authors.forename: Yongyuth
authors.initials: Y
authors.lastname: Yuthavong
authors.affiliation: ∞Department of Biochemistry and Center of Excellence in Protein Structure and Function, Faculty of Science, Mahidol University, 272 Rama VI Road, Bangkok 10400, Thailand.
authors.forename: Pimchai
authors.initials: P
authors.lastname: Chaiyen
authors.affiliation: ∥Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004351:Drug Resistance / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D012696:Glycine Hydroxymethyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000187:drug effects; D030781:Organisms, Genetically Modified; D010962:Plasmodium berghei / Q000187:drug effects / Q000472:pathogenicity; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D010966:Plasmodium vivax / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D011720:Pyrazoles / Q000737:chemistry; D051381:Rats
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D012696:Glycine Hydroxymethyltransferase