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Title: Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures
Authors: Geoffrey Schwertz
Matthias C. Witschel
Matthias Rottmann
Roger Bonnert
Ubolsree Leartsakulpanich
Penchit Chitnumsub
Aritsara Jaruwat
Wanwipa Ittarat
Anja Schäfer
Raphael A. Aponte
Susan A. Charman
Karen L. White
Abhijit Kundu
Surajit Sadhukhan
Mel Lloyd
Gail M. Freiberg
Myron Srikumaran
Marc Siggel
Adrian Zwyssig
Pimchai Chaiyen
François Diederich
ETH Zurich
Swiss Tropical and Public Health Institute (Swiss TPH)
Universitat Basel
Medicines for Malaria Venture
Thailand National Center for Genetic Engineering and Biotechnology
Monash University
TCG Lifesciences Ltd.
Covance Inc.
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 22-Jun-2017
Citation: Journal of Medicinal Chemistry. Vol.60, No.12 (2017), 4840-4860
Abstract: © 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.
ISSN: 15204804
Appears in Collections:Scopus 2016-2017

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