A concise synthesis of N-substituted fagomine derivatives and the systematic exploration of their α-glycosidase inhibition

•A novel and concise scheme for the syntheses of target compounds has been developed.•Systematic investigation of α-glycosidase inhibition has been carried on.•Structure–activity relationship was deeply discussed.•The SAR is carefully explained by molecular docking analysis.

A novel and concise scheme has been developed successfully for the syntheses of N-substituted fagomine derivatives. The transformation of lactone (2) to 1,5-diol (3) was carried on with high yield (93–95%). The cyclization of 4 to 5 is a high stereoselective reaction (de value > 98%). It is disclosed that bulky substituent at N atom of the piperidine decreases the inhibition activity except those substituents having the ability of solvation or forming disulfide bond with M444 at the active site of α-glycosidase, which enhance the interaction with enzyme. Compounds with S-configuration at C-3 show greater activity than those with R-configuration. The structure–activity relationship study is also supported by molecular docking analysis.

Graphical abstractA novel and concise scheme has been developed for the syntheses of fagomine derivatives. Systematic investigation of α-glycosidase inhibition including molecular docking analysis has been carried on.Figure optionsDownload full-size imageDownload as PowerPoint slide