Quaternary Indolizidine and Indolizidone Iminosugars as Potential Immunostimulating and Glycosidase Inhibitory Agents: Synthesis, Conformational Analysis, Biological Activity, and Molecular Docking Study

New quaternary indolizidine iminosugars,
with hydroxymethyl group
at the ring junction, namely, C-8a-hydroxymethyl-1-deoxycastano­spermine
congeners 1a, 2a, 3a and their
3-oxo analogs 1b, 2b, and 3b were synthesized by using intramolecular reductive aminocyclization/lactamization
of d-mannose/d-glucose derived C5-γ-azido
esters as a key step wherein both the rings of the indolizidine skeleton
were built up in one pot following the cascade reaction pathway. The
conformations (5C8 or 8C5) of 1–3 were assigned on the basis
of the 1H NMR studies. All compounds were found to be potent
inhibitors of various glycosidase enzymes with Ki and IC50 values in the micromolar/nanomolar concentration
range and further substantiated by molecular docking studies. The
effect of synthesized iminosugars 1–3 on the cytokine secretion of IL-4, IL-6, and IFN-γ was evaluated.
All compounds were found to be TH1 bias increasing the
TH1/TH2 cytokines ratio (IL-6 and IL-4) indicating
their potency as immunostimulating agents. Our study suggests that
immunomodulatory activity of indolizidine iminosugars can be tuned
by minor structural/stereochemical alterations.