Publication: Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold
2
Issued Date
2018-05-08
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ISSN
18607187
18607179
18607179
Other identifier(s)
2-s2.0-85045405535
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Mahidol University
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SCOPUS
Bibliographic Citation
ChemMedChem. Vol.13, No.9 (2018), 931-943
Suggested Citation
Geoffrey Schwertz, Matthias C. Witschel, Matthias Rottmann, Ubolsree Leartsakulpanich, Penchit Chitnumsub, Aritsara Jaruwat, Watcharee Amornwatcharapong, Wanwipa Ittarat, Anja Schäfer, Raphael A. Aponte, Nils Trapp, Pimchai Chaiyen, François Diederich Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold. ChemMedChem. Vol.13, No.9 (2018), 931-943. doi:10.1002/cmdc.201800053 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/45169
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Title
Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold
Abstract
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 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 Plasmodium falciparum (Pf) SHMT (14–76 nm) and cellular potencies in the low nanomolar range (165–334 nm) were measured together with interesting selectivity against human cytosolic SHMT1 (hSHMT1). Four co-crystal structures with Plasmodium vivax (Pv) 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.