Geoffrey SchwertzMatthias C. WitschelMatthias RottmannUbolsree LeartsakulpanichPenchit ChitnumsubAritsara JaruwatWatcharee AmornwatcharapongWanwipa IttaratAnja SchäferRaphael A. AponteNils TrappPimchai ChaiyenFrançois DiederichVidyasirimedhi Institute of Science and TechnologyETH ZürichUniversitat BaselSwiss Tropical and Public Health Institute (Swiss TPH)Mahidol UniversityThailand National Center for Genetic Engineering and BiotechnologyBASF SE2019-08-232019-08-232018-05-08ChemMedChem. Vol.13, No.9 (2018), 931-94318607187186071792-s2.0-85045405535https://repository.li.mahidol.ac.th/handle/123456789/45169© 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyChemistryPharmacology, Toxicology and PharmaceuticsArticleSCOPUS10.1002/cmdc.201800053