Synthesis of NAM-thiazoline derivatives as novel O-GlcNAcase inhibitors.

Human O-GlcNAcase (GH 84) and human β-N-acetyl-D-hexosaminidase (GH 20) from Homo sapiens are two therapeutic enzyme targets that share the same catalytic mechanism but play different physiological roles in vivo. Selective inhibition toward one of these enzymes is therefore of importance to regulate the corresponding bioprocess. Here ten new NAM-thiazoline derivatives were synthesized and subsequently characterized by NMR and HRMS. A preliminary bioassay showed that most of the synthesized compounds exhibited obvious selective inhibition against human O-GlcNAcase over human β-N-acetyl-D-hexosaminidase. Among the compounds tested, compound 7d (IC50 = 6.4 µM, hOGA; IC50>1 mM, hHex) and 7f (IC50 = 11.9 µM, hOGA; IC50>1 mM, hHex) proved to be a highly selective and potent inhibitor. Structure-activity relationship analysis indicated a correlation between the inhibitory activity and the size of the groups linked to the thiazoline ring.