Design, synthesis and glycosidase inhibition of C-4 branched LAB and DAB derivatives

Two series of C-4 alkylated and arylated LAB (1,4-dideoxy-1,4-imino-L-arabinitol) and DAB (1,4- dideoxy-1,4-imino-D-arabinitol) derivatives, synthesized in 6 steps from enantiomeric cyclic nitrones derived from L- and D-tartaric acid, were designed and assayed against various glycosidases. C-4 Branched LAB alkyl and phenyl derivatives 5La-d showed potent alpha-glucosidase inhibition, particularly against human lysosomal acid alpha-glucosidase; C-4 DAB derivatives 5Da-d, with small alkyl groups, showed enhanced inhibition of rat intestinal maltase and sucrase. Both enantiomeric C-4 arylated derivatives 5Lf-l and 5Df-l exhibited potent and selective alpha-glucosidase inhibition; and compound 5Li with a para-electron donating group (EDG) on its C-4 aryl group, showed the most potent rat intestinal sucrase inhibition. Docking studies showed similar hydrogen bonding modes for the iminosugar skeletons of DAB (1) and LAB (2) with ntMGAM,. While C-4 alkylated LAB derivatives showed high similarity in their binding modes with the active site of ntMGAM, binding modes of the DAB derivatives relied on the size of C-4 alkyl groups with methyl and butyl showed the optimum interactions. Furthermore, C-4 arylation improved the interactions of LAB derivatives with enzymes by T-shaped pi-pi stack with residue Trp-406; for C-4 arylated DAB derivatives, the pi-pi stack interactions were found with distinct planar distortions caused by EDGs or EWGs on the C-4 aryls. The results reported herein provided insights for the design and development of DAB and LAB related alpha-glucosidase inhibitors, and may also contribute to the future development of anti-viral, anti-diabetic and anti-Pompe disease drugs. (c) 2022 Elsevier Masson SAS. All rights reserved.

Automated summary

This study designed and synthesized two series of C-4 alkylated and arylated LAB and DAB derivatives, and evaluated their activity against various glycosidases. The results revealed potential inhibitory effects of some derivatives and provided guidance for drug design and development.