Publication: Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs
Issued Date
2017-10-12
Resource Type
ISSN
15213765
09476539
09476539
Other identifier(s)
2-s2.0-85030321240
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
Chemistry - A European Journal. Vol.23, No.57 (2017), 14345-14357
Suggested Citation
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 Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs. Chemistry - A European Journal. Vol.23, No.57 (2017), 14345-14357. doi:10.1002/chem.201703244 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/42196
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs
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.