Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold. (14th April 2018)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: ChemMedChem. Volume 13:Number 9(2018)
• Page Start: 931
• Page End: 943
• Publication Date: 2018-04-14
• Subjects: co-crystal structures -- inhibitors -- malaria -- serine hydroxymethyltransferase -- spiro compounds; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800053
• Languages: English
• ISSNs: 1860-7179

Abstract

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 ( 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. Abstract : Curved analogues : Potent antimalarial inhibitors of the enzyme serine hydroxymethyltransferase that feature a spirocyclic core were uncovered by structure‐based design. The binding mode of these novel active substances was elucidated by X‐ray co‐crystal structures, which reveal the key contribution of the vinylogous cyanamide fragment and a substantial curving of the core induced by the spirocyclic motif.