Design and synthesis of C-2 substituted thiazolo and dihydrothiazolo ring-fused 2-pyridones: pilicides with increased antivirulence activity.

TitleDesign and synthesis of C-2 substituted thiazolo and dihydrothiazolo ring-fused 2-pyridones: pilicides with increased antivirulence activity.
Publication TypeJournal Article
Year of Publication2010
AuthorsChorell, E., J. S. Pinkner, G. Phan, S. Edvinsson, F. Buelens, H. Remaut, G. Waksman, S. J. Hultgren, and F. Almqvist
JournalJ Med Chem
Volume53
Issue15
Pagination5690-5
Date Published2010 Aug 12
ISSN1520-4804
KeywordsAnti-Bacterial Agents, Binding Sites, Biofilms, Crystallography, X-Ray, Escherichia coli, Escherichia coli Proteins, Fimbriae, Bacterial, Hemagglutination Tests, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Chaperones, Molecular Structure, Periplasmic Proteins, Protein Subunits, Pyridones, Structure-Activity Relationship, Thiazoles, Virulence
Abstract

Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Experimental evaluation showed that proper substitution of this position affected the biological activity of the compound. Aryl substituents resulted in pilicides with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was determined by X-ray crystallography.

DOI10.1021/jm100470t
Alternate JournalJ. Med. Chem.
PubMed ID20586493
PubMed Central IDPMC2963145
Grant ListAI029549 / AI / NIAID NIH HHS / United States
AI048689 / AI / NIAID NIH HHS / United States
AI049950 / AI / NIAID NIH HHS / United States
DK086378 / DK / NIDDK NIH HHS / United States
R01 AI029549-20 / AI / NIAID NIH HHS / United States
R01 AI029549-21 / AI / NIAID NIH HHS / United States
R01 AI048689 / AI / NIAID NIH HHS / United States
R01 AI048689-10 / AI / NIAID NIH HHS / United States
R01 AI048689-11 / AI / NIAID NIH HHS / United States
R01 AI049950 / AI / NIAID NIH HHS / United States
R01 AI049950-08 / AI / NIAID NIH HHS / United States
R01 AI049950-09 / AI / NIAID NIH HHS / United States
R37 AI029549 / AI / NIAID NIH HHS / United States
R37 AI029549-17 / AI / NIAID NIH HHS / United States
RC1 DK086378 / DK / NIDDK NIH HHS / United States
RC1 DK086378-01 / DK / NIDDK NIH HHS / United States