Design, synthesis and biological evaluation of 3′-benzylated analogs of 3′-epi-neoponkoranol as potent α-glucosidase inhibitors

Abstract A group of 3′- epi -neoponkoranol analogs with different hydrophobic substituents attached at 3′-position of side chain moiety were designed and synthesized in order to further improve the inhibitory activities against α-glucosidases. Biological evaluation of these compounds revealed that sulfonium salts attached with ortho -substituted benzyl groups showed best α-glucosidase inhibitory activities. The most potent compound 10i showed greater inhibitory activities than all natural products. Moreover, docking studies on 10i with ntMGAM presented a new binding mode, indicating that amino residue Asp542 should be the key interacting point for strong inhibitory activity of small molecules against α-glucosidase enzymes. The strongest α-glucosidase inhibitory activity of 10i could be rationalized by van der Waals interactions between the 3′-attached substituent and particularly the ortho -substituted trifluoromethyl on benzyl group with the adjacent hydrophobic amino residues. Cytotoxicity evaluation assay demonstrated a high level of safety profile of the synthesized sulfonium salts against normal cell line. The enzyme kinetic studies showed a fully competitive inhibition of these sulfonium salts on each α-glucosidase.