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

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. Show more