Based on our previous studies that benzimidazole-fused tricyclic iminosugars 1 and 2derived fromD-ribose inhibitedβ-glucosidase significantly, a series of novel tricyclic iminosugars 6a~6c and 7a~7c derived fromL -ribose and 2-deoxy-D-ribose, respectively, were designed and synthesized through the key Mitsunobu reaction. Additionally, based on the drug design method of isosterism, a series of tricyclic iminosugars derivitives 13a,13b and 17a~17e containing amino group on C-2 position, and 28a and 28b with alkoxyl group on C-4 position on sugar ring were designed. Compounds 13a and 13b were synthesized through substitution reaction of benzylamine and methylsulfonide hydroxy (OMs), while compounds 17a~17e were prepared through ring opened reaction of amine and the three-membered epoxy intermediate 15, compounds 28a and 28b were synthesized through nucleophilic substitution reaction of 4-OH and halohydrocarbon. The inhibitory activities of compounds 6a~6c,7a~7c,13a,13b,15,17a~17e,19,28a and 28bagainstα-glucosidase (Aspergillus niger),β-glucosidase (almonds) andα-galatosidase (coffee beans) were tested. The results showed that the tested compounds exhibited no or weakα-glucosidase andα-galatosidase inhibitory activities at 10 μmol/L. Some compounds exhibited good inhibitory activities againstβ-glucosidase. Among them, the epoxy intermediate 15 and compound 17a(2-amino) were the best ones with IC₅₀values of 10.5 and 11.7 μmol/L, respectively, but lower than that of the positive control 1. The results further suggested that such fused tricyclic iminosugars were the excellent and specific inhibitors againstβ-glucosidase.

Key words: fused tricyclic iminosugar, Mitsunobu reaction, glycosidase inhibitors, benzimidazole, epoxy intermediate