Title | Design and synthesis of C-2 substituted thiazolo and dihydrothiazolo ring-fused 2-pyridones: pilicides with increased antivirulence activity. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Chorell, E., J. S. Pinkner, G. Phan, S. Edvinsson, F. Buelens, H. Remaut, G. Waksman, S. J. Hultgren, and F. Almqvist |
Journal | J Med Chem |
Volume | 53 |
Issue | 15 |
Pagination | 5690-5 |
Date Published | 2010 Aug 12 |
ISSN | 1520-4804 |
Keywords | Anti-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. |
DOI | 10.1021/jm100470t |
Alternate Journal | J. Med. Chem. |
PubMed ID | 20586493 |
PubMed Central ID | PMC2963145 |
Grant List | AI029549 / 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 |
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