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 <b>1a</b>, <b>2a</b>, <b>3a</b> and their 3-oxo analogs <b>1b</b>, <b>2b</b>, and <b>3b</b> 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 <b>1</b>–<b>3</b> were assigned on the basis of the ¹H NMR studies. All compounds were found to be potent inhibitors of various glycosidase enzymes with <i>K</i>_i and IC₅₀ values in the micromolar/nanomolar concentration range and further substantiated by molecular docking studies. The effect of synthesized iminosugars <b>1</b>–<b>3</b> on the cytokine secretion of IL-4, IL-6, and IFN-γ was evaluated. All compounds were found to be T_H1 bias increasing the T_H1/T_H2 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