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

ACS Omega
Shrawan R ChavanDilip D Dhavale

Abstract

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.

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Citations

Jan 12, 2019·Organic & Biomolecular Chemistry·Venkatesan SanthanamNamakkal G Ramesh
Apr 8, 2020·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Min LiXiao-Liu Li
Nov 25, 2020·Journal of Enzyme Inhibition and Medicinal Chemistry·Ana I Ahuja-CasarínJosé G Fernández-Bolaños
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Francesca BeginiDiego Alves
Oct 15, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Andreas WolfsgruberTanja M Wrodnigg

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Methods Mentioned

BETA
NMR
X-ray
column chromatography
Assay
ELISA
confocal microscopy

Software Mentioned

Autogrid
Spartan
Autodock
GROMOS43B1
Mercury
MODELER
PyMol Molecular Graphics System
PyMol visualize (
Spartan ’

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