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Title: Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold
Authors: 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
Vidyasirimedhi Institute of Science and Technology
ETH Zürich
Universitat Basel
Swiss Tropical and Public Health Institute (Swiss TPH)
Mahidol University
Thailand National Center for Genetic Engineering and Biotechnology
Keywords: Biochemistry, Genetics and Molecular Biology;Chemistry;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 8-May-2018
Citation: ChemMedChem. Vol.13, No.9 (2018), 931-943
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.
ISSN: 18607187
Appears in Collections:Scopus 2018

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