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

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 enzym...

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Published in:	European journal of medicinal chemistry Vol. 46; no. 9; pp. 4419 - 4429
Main Authors:	Braun, Stephan, Botzki, Alexander, Salmen, Sunnhild, Textor, Christian, Bernhardt, Günther, Dove, Stefan, Buschauer, Armin
Format:	Journal Article
Language:	English
Published:	Kidlington Elsevier Masson SAS 01-09-2011 Elsevier
Subjects:	Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Bacteria - enzymology Benzimidazole-2-thiones Benzimidazoles - chemistry Benzimidazoles - pharmacology Benzoxazole-2-thiones Benzoxazoles - chemistry Benzoxazoles - pharmacology Biological and medical sciences Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Hyaluronan lyase inhibitors Magnetic Resonance Spectroscopy Medical sciences Models, Molecular Pharmacology. Drug treatments Polysaccharide-Lyases - antagonists & inhibitors Spectrometry, Mass, Electrospray Ionization Streptococcus agalactiae Structure-Activity Relationship Structure-based design Benzimidazole-2-thiones Vcpal DMSO CTAB Vc Benzoxazole-2-thiones ECM BSA SagHyal 4755 TCDI THF Structure-based design DMAP HA SpnHyal Hyaluronan lyase inhibitors Streptococcus agalactiae DMF Hyal Polysaccharide-lyases Enzyme Nitrogen heterocycle Enzyme inhibitor Lyases In vitro Streptococcaceae Hyaluronate lyase Structure activity relation Bicyclic compound Bacteria Micrococcales Aromatic compound Antibacterial agent Chemical synthesis Carbon-oxygen lyases Oxygen nitrogen heterocycle
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Summary:	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. [Display omitted] ► We derived new leads for inhibition of streptococcal hyaluronan lyases. ► Hyaluronan lyase–ligand complexes were used for structure-based design. ► As result, we analyzed 1-acylated benzimidazole-2-thiones and benzoxazole-2-thiones. ► N-(3-Phenylpropionyl)benzoxazole-2-thione was the most potent SagHyal inhibitor. ► The structure–activity relationships correspond to the suggested binding mode.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0223-5234 1768-3254
DOI:	10.1016/j.ejmech.2011.07.014