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Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold
Author(s) -
Schwertz Geoffrey,
Witschel Matthias C.,
Rottmann Matthias,
Leartsakulpanich Ubolsree,
Chitnumsub Penchit,
Jaruwat Aritsara,
Amornwatcharapong Watcharee,
Ittarat Wanwipa,
Schäfer Anja,
Aponte Raphael A.,
Trapp Nils,
Chaiyen Pimchai,
Diederich François
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800053
Subject(s) - serine hydroxymethyltransferase , druggability , stereochemistry , chemistry , enzyme , plasmodium falciparum , serine , active site , biochemistry , biology , malaria , immunology , gene
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 n m ) and cellular potencies in the low nanomolar range (165–334 n m ) were measured together with interesting selectivity against human cytosolic SHMT1 ( h SHMT1). 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.