Please use this identifier to cite or link to this item:
http://repository.li.mahidol.ac.th/dspace/handle/123456789/41854
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 BASF SE 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. AbbVie 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. |
URI: | https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85021175260&origin=inward http://repository.li.mahidol.ac.th/dspace/handle/123456789/41854 |
ISSN: | 15204804 00222623 |
Appears in Collections: | Scopus 2016-2017 |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.