Iminosugars Spiro-Linked with Morpholine-Fused 1,2,3-Triazole: Synthesis, Conformational Analysis, Glycosidase Inhibitory Activity, Antifungal Assay, and Docking Studies

Synthesis
of iminosugars 1, 2, 3a, and 4a and N-alkyl (ethyl, butyl, hexyl,
octyl, decyl, and dodecyl) derivatives 3b–g and 4b–g spiro-linked with
morpholine-fused 1,2,3-triazole is described. Conformation of the
piperidine ring in each spiro-iminosugar was evaluated by 1H NMR spectroscopy, and conformational change in N-alkylated compounds 4b–g with respect to parent spiro-iminosugar 4a is supported by density functional theory calculations.
Out of 16 new spiro-iminosugars, the spiro-iminosugars 3a (IC50 = 0.075 μM) and 4a (IC50 = 0.036 μM) were found to be more potent inhibitors of α-glucosidase
than the marketed drug miglitol (IC50 = 0.100 μM).
In addition, 3a (minimum inhibition concentration (MIC)
= 0.85 μM) and 4a (MIC = 0.025 μM) showed
more potent antifungal activity against Candida albicans than antifungal drug amphotericin b (MIC = 1.25 μM). In few
cases, the N-alkyl derivatives showed increase of α-glucosidase
inhibition and enhancement of antifungal activity compare to the respective
parent iminosugar. The biological activities were further substantiated
by molecular docking studies.