Design of benzimidazole- and benzoxazole-2-thione derivatives as inhibitors of bacterial hyaluronan lyase.

Stephan Braun, Alexander Botzki, Sunnhild Salmen, Christian Textor, Günther Bernhardt, Stefan Dove, Armin Buschauer

Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany.

European journal of medicinal chemistry 2011 Sep

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Bacterial hyaluronan lyases (Hyal) degrade hyaluronan, an important component of the extracellular matrix, and are involved in microbial spread. Hyal inhibitors may serve as tools to study the role of the enzyme, its substrates and products in the course of bacterial infections. Moreover, such enzyme inhibitors are potential candidates for antibacterial combination therapy. Based on crystal structures of Streptococcus pneumoniae Hyal in complex with a hexasaccharide substrate and with different inhibitors, 1-acylated benzimidazole-2-thiones and benzoxazole-2-thiones were derived as new leads for the inhibition of Streptococcus agalactiae strain 4755 Hyal. Structure-based optimization led to N-(3-phenylpropionyl)benzoxazole-2-thione, one of the most potent compounds known to date (IC(50) values: 24 μM at pH 7.4, 15 μM at pH 5). Among the 27 new derivatives, other N-acylated benzimidazoles and benzoxazoles are just as active at pH 7.4, but not at pH 5. The results support a binding mode characterized by interactions with residues in the catalytic site and with a hydrophobic patch. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Citation

Stephan Braun, Alexander Botzki, Sunnhild Salmen, Christian Textor, Günther Bernhardt, Stefan Dove, Armin Buschauer. Design of benzimidazole- and benzoxazole-2-thione derivatives as inhibitors of bacterial hyaluronan lyase. European journal of medicinal chemistry. 2011 Sep;46(9):4419-29