NAG-thiazoline is a strong competitive inhibitor of GH20 β-N-acetyl- hexosaminidases and GH84 β-N-acetylglucosaminidases. Here, we focused on the design, synthesis and inhibition potency of a series of new derivatives of NAG-thiazoline modified at the C-6 position. Dimerization of NAG-thiazoline via C-6 attached triazole linkers prepared by click chemistry was employed to make use of multivalency in the inhibition. Novel compounds were tested as potential inhibitors of β-N-acetylhexosaminidases from Talaromyces flavus, Streptomyces plicatus (both GH20) and β-N-acetylglucosaminidases from Bacteroides thetaiotaomicron and humans (both GH84). From the set of newly prepared NAG-thiazoline derivatives, only C-6-azido-NAG-thiazoline displayed inhibition activity towards these enzymes; C-6 triazole-substituted NAG-thiazolines lacked inhibition activity against the enzymes used. Docking of C-6-azido-NAG-thiazoline into the active site of the tested enzymes was performed. Moreover, a stability study with GlcNAc-thiazoline confirmed its decomposition at pH < 6 yielding 2-acetamido-2-deoxy-1-thio-α/β-D-glucopyranoses, which presumably dimerize oxidatively into S-S linked dimers; decomposition products of NAG-thiazoline are void of inhibitory activity.

• MeSH
• Acetylglucosamine analogs & derivatives   chemical synthesis   chemistry   pharmacology   MeSH
• beta-N-Acetylhexosaminidases antagonists & inhibitors   chemistry   metabolism   MeSH
• Glycoside Hydrolases antagonists & inhibitors   chemistry   metabolism   MeSH
• Catalytic Domain MeSH
• Molecular Conformation MeSH
• Models, Molecular MeSH
• Drug Stability MeSH
• Thiazoles chemical synthesis   chemistry   pharmacology   MeSH
• Protein Binding MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylglucosamine MeSH
• beta-N-Acetylhexosaminidases MeSH
• Glycoside Hydrolases MeSH
• hexosaminidase C MeSH Browser
• N-acetylglucosamine thiazoline MeSH Browser
• Thiazoles MeSH