Potent Inhibitors of <i>Plasmodial</i> Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold
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- Geoffrey Schwertz
- Laboratorium für Organische Chemie ETH Zürich Vladimir-Prelog-Weg 3 8093 Zürich Switzerland
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- Matthias C. Witschel
- BASF SE Carl-Bosch-Strasse 38 67056 Ludwigshafen Germany
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- Matthias Rottmann
- Swiss Tropical and Public Health Institute (SwissTPH) Socinstrasse 57 4051 Basel Switzerland
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- Ubolsree Leartsakulpanich
- National Center for Genetic Engineering and Biotechnology 113 Thailand Science Park, Phahonyothin Road Pathumthani 12120 Thailand
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- Penchit Chitnumsub
- National Center for Genetic Engineering and Biotechnology 113 Thailand Science Park, Phahonyothin Road Pathumthani 12120 Thailand
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- Aritsara Jaruwat
- National Center for Genetic Engineering and Biotechnology 113 Thailand Science Park, Phahonyothin Road Pathumthani 12120 Thailand
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- Watcharee Amornwatcharapong
- Department of Biochemistry and Center for Excellence in Protein and Enzyme Technology, Faculty of Science Mahidol University 272 Rama VI Road Bangkok 10400 Thailand
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- Wanwipa Ittarat
- National Center for Genetic Engineering and Biotechnology 113 Thailand Science Park, Phahonyothin Road Pathumthani 12120 Thailand
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- Anja Schäfer
- Swiss Tropical and Public Health Institute (SwissTPH) Socinstrasse 57 4051 Basel Switzerland
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- Raphael A. Aponte
- BASF SE Carl-Bosch-Strasse 38 67056 Ludwigshafen Germany
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- Nils Trapp
- Laboratorium für Organische Chemie ETH Zürich Vladimir-Prelog-Weg 3 8093 Zürich Switzerland
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- Pimchai Chaiyen
- Department of Biochemistry and Center for Excellence in Protein and Enzyme Technology, Faculty of Science Mahidol University 272 Rama VI Road Bangkok 10400 Thailand
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- François Diederich
- Laboratorium für Organische Chemie ETH Zürich Vladimir-Prelog-Weg 3 8093 Zürich Switzerland
書誌事項
- 公開日
- 2018-04-14
- 権利情報
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- http://onlinelibrary.wiley.com/termsAndConditions#vor
- DOI
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- 10.1002/cmdc.201800053
- 公開者
- Wiley
この論文をさがす
説明
<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>
収録刊行物
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- ChemMedChem
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ChemMedChem 13 (9), 931-943, 2018-04-14
Wiley
