Synthesis of C/C-cyclitols and CN-aminocyclitols from maltose and X-ray crystal structure of GlgEI V279S in a complex with an amylostatin GXG-like derivative.

C/C-cyclitols and CN-aminocyclitols find applications in the pharmaceutical sector as α-glucosidase inhibitors and in the agricultural sector as fungicides and insecticides. In this study, we identified C/C-cyclitols and CN-aminocyclitols as potential inhibitors of () GlgEI-V279S based on the docking scores. The protein and the ligand (targets , , and ) were prepared, the states were generated at pH 7.0 ± 2.0, and the ligands were docked into the active sites of the receptor Glide™. The synthetic route to these targets was similar to our previously reported route used to obtain 4-⍺-glucoside of valienamine (), except the protecting group for target was a -bromobenzyl (PBB) ether to preserve the alkene upon deprotection. While compounds - did not inhibit GlgEI-V279S at the concentrations evaluated, an X-ray crystal structure of the GlgE1-V279S/ complex was solved to a resolution of 2.73 Å. This structure allowed assessment differences and commonality with our previously reported inhibitors and was useful for identifying enzyme-compound interactions that may be important for future inhibitor development. The Asp 394 nucleophile formed a bidentate hydrogen bond interaction with the exocyclic oxygen atoms (C(3)-OH and C(7)-OH) similar to the observed interactions with the GlgEI-V279S in a complex with (PDB:7MGY). In addition, the data suggest replacing the cyclohexyl group with more isosteric and hydrogen bond-donating groups to increase binding interactions in the + 1 binding site.