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

• Published in: European journal of medicinal chemistry 2022-04, Vol.233, p.114230-114230, Article 114230
• Main Authors: Wang, Jun-Zhe, Cheng, Bin, Kato, Atsushi, Kise, Maki, Shimadate, Yuna, Jia, Yue-Mei, Li, Yi-Xian, Fleet, George W.J., Yu, Chu-Yi
• Format: Article
• Language: English
• Subjects: C-4 branched; Docking studies; Glycosidase inhibition; Iminosugar; LAB and DAB (1,4-dideoxy-1,4-imino-d/l-arabinitol) derivatives; Structure-activity relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114230

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 α-glucosidase inhibition, particularly against human lysosomal acid α-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 α-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 π-π stack with residue Trp-406; for C-4 arylated DAB derivatives, the π-π 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 α-glucosidase inhibitors, and may also contribute to the future development of anti-viral, anti-diabetic and anti-Pompe disease drugs. [Display omitted] •C-4 alkylated and arylated LAB and DAB derivatives have been synthesized from nitrones.•The two series derivatives showed high selectivity to α-glucosidase.•The C-4 alkyl and aryl groups have significant influences on inhibitory activities.•Docking studies showed different binding modes of the LAB and DAB derivatives.