Geoffrey SchwertzMatthias C. WitschelMatthias RottmannRoger BonnertUbolsree LeartsakulpanichPenchit ChitnumsubAritsara JaruwatWanwipa IttaratAnja SchäferRaphael A. AponteSusan A. CharmanKaren L. WhiteAbhijit KunduSurajit SadhukhanMel LloydGail M. FreibergMyron SrikumaranMarc SiggelAdrian ZwyssigPimchai ChaiyenFrançois DiederichETH ZurichBASF SESwiss Tropical and Public Health Institute (Swiss TPH)Universitat BaselMedicines for Malaria VentureThailand National Center for Genetic Engineering and BiotechnologyMonash UniversityTCG Lifesciences Ltd.Covance Inc.AbbVieMahidol University2018-12-212019-03-142018-12-212019-03-142017-06-22Journal of Medicinal Chemistry. Vol.60, No.12 (2017), 4840-486015204804002226232-s2.0-85021175260https://repository.li.mahidol.ac.th/handle/20.500.14594/41854© 2017 American Chemical Society. Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 Å resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-Aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1021/acs.jmedchem.7b00008