Design and Synthesis of C-2 Substituted Thiazolo and Dihydrothiazolo Ring-Fused 2-Pyridones: Pilicides with Increased Antivirulence Activity

被引：80

作者：

Chorell, Erik ^{[2
]}

Pinkner, Jerome S. ^{[1
]}

Phan, Gilles ^{[3
]}

Edvinsson, Sofie ^{[2
]}

Buelens, Floris ^{[3
]}

Remaut, Han ^{[3
,4
]}

Waksman, Gabriel ^{[3
]}

Hultgren, Scott J. ^{[1
]}

Almqvist, Fredrik ^{[2
]}

机构：

[1] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA

[2] Umea Univ, Dept Chem, SE-90187 Umea, Sweden

[3] Univ London Birkbeck Coll, Inst Struct & Mol Biol, London WC1E 7HX, England

[4] Vrije Univ Brussel VIB, Dept Cellular & Mol Interact, Lab Struct & Mol Microbiol, B-1050 Brussels, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 15期

关键词：

UROPATHOGENIC ESCHERICHIA-COLI; INHIBIT PILUS BIOGENESIS; CHAPERONE-USHER PATHWAY; BICYCLIC; 2-PYRIDONES; TARGETING VIRULENCE; FIBER FORMATION; OUTER-MEMBRANE; FUNCTIONALIZATION; BACTERIA; BIOLOGY;

D O I：

10.1021/jm100470t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 pill-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was determined by X-ray crystallography.

引用

页码：5690 / 5695

页数：6

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