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Carbohydr Res. 2019 Sep 6;485:107807. doi: 10.1016/j.carres.2019.107807. [Epub ahead of print]

Synthesis of tricyclic benzimidazole-iminosugars as potential glycosidase inhibitors via a Mitsunobu reaction.

Author information

1
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding, 071002, China.
2
Department of Epidemiology and Health Statistics, College of Public Health, Hebei University, Baoding, 071002, China.
3
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding, 071002, China. Electronic address: lixl@hbu.edu.cn.
4
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding, 071002, China. Electronic address: hua-todd@163.com.

Abstract

A series of tricyclic benzimidazole-iminosugars 1(a-f) and 2(a-f) were synthesized and evaluated for their their inhibitory activities against five glycosidases. The synthesis initiated from the benzyl protected sugar (aldehyde) 5 that reacted with 1,2-diaminobenzene to afford aldo-benzimidazole 6 by the iodine-induced oxidative condensation. Then, tricyclic compound 7 was obtained in high yields of 73%-87% by the key Mitsunobu reaction through intramolecular cyclization of the unprotected OH and the NH in 6. After removal of the benzyl group in CF3SO3H, the target tricyclic benzimidazole-iminosugars 1 and 2 were achieved. The protocol was effective for the preparation of the tricyclic iminosugar in satisfactory yield. The results of the glycosidase inhibitory activities of 1 and 2 showed that three compounds derived from d-ribose exhibited specific and good inhibitory effects on β-glucosidase. Among them, 1e-1 was the best one with IC50 value of 5.37 μM. All hydroxyl groups on β-position would be favourable to the inhibitory activity of such tricyclic benzimidazole-iminosugars against β-glucosidase.

KEYWORDS:

Benzimidazole; Glycosidase inhibitory activity; Iodine-induced oxidative condensation; Mitsunobu reaction; Tricyclic iminosugars

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