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Title: Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs
Authors: Geoffrey Schwertz
Michelle S. Frei
Matthias C. Witschel
Matthias Rottmann
Ubolsree Leartsakulpanich
Penchit Chitnumsub
Aritsara Jaruwat
Wanwipa Ittarat
Anja Schäfer
Raphael A. Aponte
Nils Trapp
Kerstin Mark
Pimchai Chaiyen
François Diederich
ETH Zurich
Swiss Tropical and Public Health Institute (Swiss TPH)
Universitat Basel
Thailand National Center for Genetic Engineering and Biotechnology
Mahidol University
Vidyasirimedhi Institute of Science and Technology
Keywords: Chemistry
Issue Date: 12-Oct-2017
Citation: Chemistry - A European Journal. Vol.23, No.57 (2017), 14345-14357
Abstract: © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Malaria remains a major threat to mankind due to the perpetual emergence of resistance against marketed drugs. Twenty-one pyrazolopyran-based inhibitors bearing terminal biphenyl, aryl sulfonamide, or aryl sulfone motifs were synthesized and tested towards serine hydroxymethyltransferase (SHMT), a key enzyme of the folate cycle. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target, as well as PfNF54 strains in cell-based assays in the low nanomolar range (18–56 nm). Seven co-crystal structures with P. vivax (Pv) SHMT were solved at 2.2–2.6 Å resolution. We observed an unprecedented influence of the torsion angle of ortho-substituted biphenyl moieties on cell-based efficacy. The peculiar lipophilic character of the sulfonyl moiety was highlighted in the complexes with aryl sulfonamide analogues, which bind in their preferred staggered orientation. The results are discussed within the context of conformational preferences in the ligands.
ISSN: 15213765
Appears in Collections:Scopus 2016-2017

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