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Target-directed Dynamic Combinatorial Chemistry: A Study on Potentials and Pitfalls as Exemplified on a Bacterial Target.
- Source :
-
Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2017 Aug 25; Vol. 23 (48), pp. 11570-11577. Date of Electronic Publication: 2017 Aug 04. - Publication Year :
- 2017
-
Abstract
- Target-directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors of pharmacologically relevant targets. In this contribution, we present an application for a bacterial target, the lectin FimH, a crucial virulence factor of uropathogenic E. coli being the main cause of urinary tract infections. A small dynamic library of acylhydrazones was formed from aldehydes and hydrazides and equilibrated at neutral pH in presence of aniline as nucleophilic catalyst. The major success factors turned out to be an accordingly adjusted ratio of scaffolds and fragments, an adequate sample preparation prior to HPLC analysis, and the data processing. Only then did the ranking of the dynamic library constituents correlate well with affinity data. Furthermore, as a support of DCC applications especially to larger libraries, a new protocol for improved hit identification was established.<br /> (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Adhesins, Escherichia coli genetics
Adhesins, Escherichia coli metabolism
Aldehydes chemistry
Aniline Compounds chemistry
Catalysis
Combinatorial Chemistry Techniques
Escherichia coli metabolism
Fimbriae Proteins genetics
Fimbriae Proteins metabolism
Hydrazones chemical synthesis
Hydrazones metabolism
Hydrogen-Ion Concentration
Small Molecule Libraries chemistry
Small Molecule Libraries metabolism
Surface Plasmon Resonance
Fimbriae Proteins antagonists & inhibitors
Hydrazones chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1521-3765
- Volume :
- 23
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- Chemistry (Weinheim an der Bergstrasse, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 28654733
- Full Text :
- https://doi.org/10.1002/chem.201701601