N-substituted iminosugar analogues are potent inhibitors of
glucosidases and
glycosyltransferases with broad therapeutic applications, such as treatment of diabetes and
Gaucher disease, immunosuppressive activities, and antibacterial and
antiviral effects against HIV, HPV,
hepatitis C, bovine
diarrhea (BVDV), Ebola (EBOV) and Marburg viruses (MARV),
influenza, Zika, and dengue virus. Based on our previous work on functionalized isomeric 1,5-dideoxy-1,5-imino-D-gulitol (L-gulo-
piperidines, with inverted configuration at C-2 and C-5 in respect to
glucose or deoxynojirimycin (DNJ)) and 1,6-dideoxy-1,6-imino-D-mannitol (D-manno-azepane derivatives) cores N-linked to different sites of glucopyranose units, we continue our studies on these alternative iminosugars bearing simple N-alkyl chains instead of
glucose to understand if these easily accessed scaffolds could preserve the inhibition profile of the corresponding
glucose-based N-alkyl derivatives as DNJ cores found in
miglustat and
miglitol drugs. Thus, a small library of iminosugars (14 compounds) displaying different stereochemistry, ring size, and N-substitutions was successfully synthesized from a common precursor,
D-mannitol, by utilizing an SN2 aminocyclization reaction via two isomeric bis-
epoxides. The evaluation of the prospective inhibitors on
glucosidases revealed that merely D-gluco-
piperidine (
miglitol, 41a) and L-ido-azepane (41b) DNJ-derivatives bearing the N-hydroxylethyl group showed inhibition towards α-
glucosidase with IC50 41 µM and 138 µM, respectively, using DNJ as reference (IC50 134 µM). On the other hand, β-
glucosidase inhibition was achieved for
glucose-inverted configuration (C-2 and C-5) derivatives, as novel L-gulo-
piperidine (27a) and D-manno-azepane (27b), preserving the N-butyl chain, with IC50 109 and 184 µM, respectively, comparable to
miglustat with the same N-butyl substituent (40a, IC50 172 µM). Interestingly, the seven-membered ring L-ido-azepane (40b) displayed near twice the activity (IC50 80 µM) of the corresponding D-gluco-
piperidine miglustat drug (40a). Furthermore, besides α-
glucosidase inhibition, both
miglitol (41a) and L-ido-azepane (41b) proved to be the strongest β-
glucosidase inhibitors of the series with IC50 of 4 µM.