{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1363951795756000000.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1002/cmdc.201800053"}},{"identifier":{"@type":"URI","@value":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fcmdc.201800053"}},{"identifier":{"@type":"URI","@value":"https://chemistry-europe.onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201800053"}}],"dc:title":[{"@value":"Potent Inhibitors of <i>Plasmodial</i> Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:title>Abstract</jats:title><jats:p>With the discovery that serine hydroxymethyltransferase (SHMT) is a druggable target for antimalarials, the aim of this study was to design novel inhibitors of this key enzyme in the folate biosynthesis cycle. Herein, 19 novel spirocyclic ligands based on either 2‐indolinone or dihydroindene scaffolds and featuring a pyrazolopyran core are reported. Strong target affinities for <jats:italic>Plasmodium falciparum</jats:italic> (<jats:italic>Pf</jats:italic>) SHMT (14–76 n<jats:sc>m</jats:sc>) and cellular potencies in the low nanomolar range (165–334 n<jats:sc>m</jats:sc>) were measured together with interesting selectivity against human cytosolic SHMT1 (<jats:italic>h</jats:italic>SHMT1). Four co‐crystal structures with <jats:italic>Plasmodium vivax</jats:italic> (<jats:italic>Pv</jats:italic>) SHMT solved at 2.2–2.4 Å resolution revealed the key role of the vinylogous cyanamide for anchoring ligands within the active site. The spirocyclic motif in the molecules enforces the pyrazolopyran core to adopt a substantially more curved conformation than that of previous non‐spirocyclic analogues. Finally, solvation of the spirocyclic lactam ring of the receptor‐bound ligands is discussed.</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1383951795756000000","@type":"Researcher","foaf:name":[{"@value":"Geoffrey Schwertz"}],"jpcoar:affiliationName":[{"@value":"Laboratorium für Organische Chemie ETH Zürich  Vladimir-Prelog-Weg 3 8093 Zürich Switzerland"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000011","@type":"Researcher","foaf:name":[{"@value":"Matthias C. Witschel"}],"jpcoar:affiliationName":[{"@value":"BASF SE  Carl-Bosch-Strasse 38 67056 Ludwigshafen Germany"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000010","@type":"Researcher","foaf:name":[{"@value":"Matthias Rottmann"}],"jpcoar:affiliationName":[{"@value":"Swiss Tropical and Public Health Institute (SwissTPH)  Socinstrasse 57 4051 Basel Switzerland"},{"@value":"Universität Basel  Petersplatz 1 4003 Basel Switzerland"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000007","@type":"Researcher","foaf:name":[{"@value":"Ubolsree Leartsakulpanich"}],"jpcoar:affiliationName":[{"@value":"National Center for Genetic Engineering and Biotechnology  113 Thailand Science Park, Phahonyothin Road Pathumthani 12120 Thailand"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000001","@type":"Researcher","foaf:name":[{"@value":"Penchit Chitnumsub"}],"jpcoar:affiliationName":[{"@value":"National Center for Genetic Engineering and Biotechnology  113 Thailand Science Park, Phahonyothin Road Pathumthani 12120 Thailand"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000005","@type":"Researcher","foaf:name":[{"@value":"Aritsara Jaruwat"}],"jpcoar:affiliationName":[{"@value":"National Center for Genetic Engineering and Biotechnology  113 Thailand Science Park, Phahonyothin Road Pathumthani 12120 Thailand"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000009","@type":"Researcher","foaf:name":[{"@value":"Watcharee Amornwatcharapong"}],"jpcoar:affiliationName":[{"@value":"Department of Biochemistry and Center for Excellence in Protein and Enzyme Technology, Faculty of Science Mahidol University  272 Rama VI Road Bangkok 10400 Thailand"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000002","@type":"Researcher","foaf:name":[{"@value":"Wanwipa Ittarat"}],"jpcoar:affiliationName":[{"@value":"National Center for Genetic Engineering and Biotechnology  113 Thailand Science Park, Phahonyothin Road Pathumthani 12120 Thailand"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000003","@type":"Researcher","foaf:name":[{"@value":"Anja Schäfer"}],"jpcoar:affiliationName":[{"@value":"Swiss Tropical and Public Health Institute (SwissTPH)  Socinstrasse 57 4051 Basel Switzerland"},{"@value":"Universität Basel  Petersplatz 1 4003 Basel Switzerland"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000012","@type":"Researcher","foaf:name":[{"@value":"Raphael A. Aponte"}],"jpcoar:affiliationName":[{"@value":"BASF SE  Carl-Bosch-Strasse 38 67056 Ludwigshafen Germany"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000006","@type":"Researcher","foaf:name":[{"@value":"Nils Trapp"}],"jpcoar:affiliationName":[{"@value":"Laboratorium für Organische Chemie ETH Zürich  Vladimir-Prelog-Weg 3 8093 Zürich Switzerland"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000004","@type":"Researcher","foaf:name":[{"@value":"Pimchai Chaiyen"}],"jpcoar:affiliationName":[{"@value":"Department of Biochemistry and Center for Excellence in Protein and Enzyme Technology, Faculty of Science Mahidol University  272 Rama VI Road Bangkok 10400 Thailand"},{"@value":"Department of Biomolecular Science and Engineering, School of Biomolecular Science & Engineering Vidyasirimedhi Institute of Science and Technology (VISTEC)  Wangchan Valley Rayong 21210 Thailand"}]},{"@id":"https://cir.nii.ac.jp/crid/1383951795756000008","@type":"Researcher","foaf:name":[{"@value":"François Diederich"}],"jpcoar:affiliationName":[{"@value":"Laboratorium für Organische Chemie ETH Zürich  Vladimir-Prelog-Weg 3 8093 Zürich Switzerland"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"18607179"},{"@type":"EISSN","@value":"18607187"}],"prism:publicationName":[{"@value":"ChemMedChem"}],"dc:publisher":[{"@value":"Wiley"}],"prism:publicationDate":"2018-04-14","prism:volume":"13","prism:number":"9","prism:startingPage":"931","prism:endingPage":"943"},"reviewed":"false","dc:rights":["http://onlinelibrary.wiley.com/termsAndConditions#vor"],"url":[{"@id":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fcmdc.201800053"},{"@id":"https://chemistry-europe.onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201800053"}],"createdAt":"2018-04-14","modifiedAt":"2025-10-12","relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360298345003502464","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"New biofunctional effects of oleanane-type triterpene saponins"}]},{"@id":"https://cir.nii.ac.jp/crid/1360848658398643840","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Design strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction"}]}],"dataSourceIdentifier":[{"@type":"CROSSREF","@value":"10.1002/cmdc.201800053"},{"@type":"CROSSREF","@value":"10.1021/acs.jnatprod.3c00815_references_DOI_Befja8otWOqxUvyiWVJukQGWZmd"},{"@type":"CROSSREF","@value":"10.1038/s41467-019-08833-7_references_DOI_Befja8otWOqxUvyiWVJukQGWZmd"}]}