Design and synthesis of novel benzimidazole-iminosugars linked a substituted phenyl group and their inhibitory activities against β-glucosidase.

A series of novel benzimidazole-iminosugars linked a (substuituted) phenyl group on benzene ring of benzimidazole 5(a-p) and 6(a-p) have been rationally designed and conveniently synthesized through Suzuki coupling reaction in high yields. All compounds have been evaluated for their inhibitory activities against β-glucosidase (almond). Six compounds 5d, 6d, 6e, 6i, 6n, and 6p showed more significant inhibitory activities with IC values in the range of 0.03-0.08 μM, almost 10-fold improved than that of the parent analogue 4, and much higher than that of the positive control castanospermine. The additional phenyl ring and the electron donating groups on it would be beneficial for the activity. Compounds 6d, 6n, and 4 had been chosen to be tested for their inhibition types against β-glucosidase. Interestingly, three compounds have different inhibition types although they had very similar structure. Their K values were calculated to be 0.02 ± 0.01 μM, 0.02 ± 0.01 μM, and 0.66 ± 0.14 μM, respectively. The equilibrium dissociation constant (K) for 6d, 6n, and 4 and β-glucosidase was 0.04 μM, 0.03 μM and 0.45 μM by the ITC-based assay, respectively. Molecular docking work suggests that such benzimidazole-iminosugars derivatives might bind to the active site of β-glucosidase mainly through hydrogen bonds, the additional phenyl ring towards the solvent-exposed region played an important effect on their inhibitory activity against β-glucosidase.