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Potent inhibitors of plasmodial serine hydroxymethyltransferase (SHMT) featuring a spirocyclic scaffold

Schwertz, Geoffrey and Witschel, Matthias C. and Rottmann, Matthias and Leartsakulpanich, Ubolsree and Chitnumsub, Penchit and Jaruwat, Aritsara and Amornwatcharapong, Watcharee and Ittarat, Wanwipa and Schäfer, Anja and Aponte, Raphael A. and Trapp, Nils and Chaiyen, Pimchai and Diederich, François. (2018) Potent inhibitors of plasmodial serine hydroxymethyltransferase (SHMT) featuring a spirocyclic scaffold. ChemMedChem, 13 (9). pp. 931-943.

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Official URL: https://edoc.unibas.ch/69225/

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Abstract

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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias and Schäfer, Anja
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:1860-7179
e-ISSN:1860-7187
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:01 Mar 2019 12:39
Deposited On:01 Mar 2019 12:39

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