Synthesis, computational study and glycosidase inhibitory activity of polyhydroxylated conidine alkaloids—a bicyclic iminosugar

Abstract

New bicyclic conidine iminosugars 1d and 1e were synthesized from D-glucose. Thus, D-glucose was converted to sugar β-amino acids 3a and 3b in good yields. Individual treatment of 3a/3b with the Mukaiyama reagent afforded sugar β-lactams 4a/4b that on reduction with LiAlH₄/AlCl₃ gave azetidines 5a/5b with a sugar appendage. Reductive aminocyclization of sugar azetidines 5a/5b afforded the corresponding conidine iminosugars 1d/1e. Based on the ¹H NMR and DFT calculation studies the conformation of 1d was assigned as half chair A2 and that of 1e as a boat B2. The glycosidase inhibitory activities of 1d and 1e such as α-mannosidase, α-glucosidase and α-galactosidase were studied. The α-amylase activity was compared with acarbose. Compound 1d was found to be a moderate inhibitor of glycosidases while 1e was noticed to be a good inhibitor of α-mannosidase and a moderate inhibitor of other glycosidases. These results were substantiated by molecular docking studies using WHAT IF software and the AUTODOCK 3.0 program.