Syntheses and biological evaluation of 2-amino-3-acyl- tetrahydrobenzothiophene derivatives; Antibacterial agents with antivirulence activity

Hung The Dang, Erik Chorell, Hanna Uvell, Jerome S. Pinkner, Scott J. Hultgren, Fredrik Almqvist

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Developing new compounds targeting virulence factors (e.g., inhibition of pilus assembly by pilicides) is a promising approach to combating bacterial infection. A high-throughput screening campaign of a library of 17500 small molecules identified 2-amino-3-acyl-tetrahydrobenzothiophene derivatives (hits 2 and 3) as novel inhibitors of pili-dependent biofilm formation in a uropathogenic Escherichia coli strain UTI89. Based on compounds 2 and 3 as the starting point, we designed and synthesized a series of structurally related analogs and investigated their activity against biofilm formation of E. coli UTI89. Systematic structural modification of the initial hits provided valuable information on their SARs for further optimization. In addition, small structural changes to the parent molecules resulted in low micromolar inhibitors (20-23) of E. coli biofilm development without an effect on bacterial growth. The hit compound 3 and its analog 20 were confirmed to prevent pili formation in a hemagglutination (HA) titer assay and electron microscopy (EM) measurements. These findings suggest that 2-amino-3-acyl-tetrahydrobenzothiophenes may serve as a new class of compounds for further elaboration as antibacterial agents with antivirulence activity.

Original languageEnglish
Pages (from-to)1942-1956
Number of pages15
JournalOrganic and Biomolecular Chemistry
Volume12
Issue number12
DOIs
StatePublished - Mar 28 2014

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