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Improvement of Aglycone π‐Stacking Yields Nanomolar to Sub‐nanomolar FimH Antagonists
Author(s) -
Schönemann Wojciech,
Cramer Jonathan,
Mühlethaler Tobias,
Fiege Brigitte,
Silbermann Marleen,
Rabbani Said,
Dätwyler Philipp,
Zihlmann Pascal,
Jakob Roman P.,
Sager Christoph P.,
Smieško Martin,
Schwardt Oliver,
Maier Timm,
Ernst Beat
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900051
Subject(s) - context (archaeology) , chemistry , substituent , stacking , stereochemistry , ligand (biochemistry) , aglycone , combinatorial chemistry , biophysics , crystallography , biochemistry , biology , receptor , organic chemistry , glycoside , paleontology
Abstract Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti‐adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium‐affinity state in the absence and a high‐affinity state in the presence of shear forces. Until recently, mostly the high‐affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low‐affinity state. In this communication, we demonstrate that fluorination of biphenyl α‐ d ‐mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub‐nanomolar K D values for the low‐ and high‐affinity states, respectively. The face‐to‐face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as 1 H, 15 N‐HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.