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

Abstract

Synthesis of iminosugars <b>1</b>, <b>2</b>, <b>3a</b>, and <b>4a</b> and N-alkyl (ethyl, butyl, hexyl, octyl, decyl, and dodecyl) derivatives <b>3b</b>-<b>g</b> and <b>4b</b>-<b>g</b> 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 <b>4b</b>-<b>g</b> with respect to parent spiro-iminosugar <b>4a</b> is supported by density functional theory calculations. Out of 16 new spiro-iminosugars, the spiro-iminosugars <b>3a</b> (IC₅₀ = 0.075 μM) and <b>4a</b> (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, <b>3a</b> (minimum inhibition concentration (MIC) = 0.85 μM) and <b>4a</b> (MIC = 0.025 μM) showed more potent antifungal activity against <i>Candida albicans</i> 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.