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Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs
Author(s) -
Schwertz Geoffrey,
Frei Michelle S.,
Witschel Matthias C.,
Rottmann Matthias,
Leartsakulpanich Ubolsree,
Chitnumsub Penchit,
Jaruwat Aritsara,
Ittarat Wanwipa,
Schäfer Anja,
Aponte Raphael A.,
Trapp Nils,
Mark Kerstin,
Chaiyen Pimchai,
Diederich François
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201703244
Subject(s) - serine hydroxymethyltransferase , aryl , sulfonyl , sulfonamide , stereochemistry , sulfone , moiety , biphenyl , chemistry , enzyme , serine , combinatorial chemistry , biochemistry , organic chemistry , alkyl
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 Pf NF54 strains in cell‐based assays in the low nanomolar range (18–56 n m ). 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.