Toward the Identification of Novel Antimicrobial Agents: One-Pot Synthesis of Lipophilic Conjugates of N-Alkyl d- and l-Iminosugars.

Anna Esposito,Stefano D'Errico,Annalisa Guaragna,Eliana De Gregorio,Daniele D'Alonzo

doi:10.3390/md18110572

Abstract

In the effort to improve the antimicrobial activity of iminosugars, we report the synthesis of lipophilic iminosugars 10a–b and 11a–b based on the one-pot conjugation of both enantiomeric forms of N-butyldeoxynojirimycin (NBDNJ) and N-nonyloxypentyldeoxynojirimycin (NPDNJ) with cholesterol and a succinic acid model linker. The conjugation reaction was tuned using the established PS-TPP/I2/ImH activating system, which provided the desired compounds in high yields (94–96%) by a one-pot procedure. The substantial increase in the lipophilicity of 10a–b and 11a–b is supposed to improve internalization within the bacterial cell, thereby potentially leading to enhanced antimicrobial properties. However, assays are currently hampered by solubility problems; therefore, alternative administration strategies will need to be devised.

Highlights

Iminosugars are naturally occurring or synthetic glycomimetics with an amino function replacing the endocyclic oxygen of the corresponding carbohydrates [1]
Over the last few decades, interesting broad-spectrum therapeutic applications have been found that have led to the development of three iminosugar drugs (Figure 1), namely Glyset (N-hydroxyethyl-deoxynojirimycin, Miglitol, 1), which is used for the therapeutic treatment of type 2 diabetes [6], Zavesca (N-butyldeoxynojirimycin, NBDNJ, 2), which is used for lysosomal storage disorders including Gaucher and Niemann–Pick type
We conceived as an activating agent the system based on the combined use of triphenyl phosphine (TPP) or its polymer-supported variant (PS-TPP), molecular iodine (I2 ) and imidazole (ImH)

Summary

Introduction

Iminosugars are naturally occurring or synthetic glycomimetics with an amino function replacing the endocyclic oxygen of the corresponding carbohydrates [1]. Thanks to their excellent ability to act as modulators (inhibitors/enhancers) of the activity of carbohydrate processing enzymes, including glycosyl hydrolases [2,3], glycosyltransferases [4] or glycogen phosphorylases [5], iminosugars can be considered as the main and best-settled class of sugar mimetics described so far. Over the last few decades, interesting broad-spectrum therapeutic applications have been found that have led to the development of three iminosugar drugs (Figure 1), namely Glyset (N-hydroxyethyl-deoxynojirimycin, Miglitol, 1), which is used for the therapeutic treatment of type 2 diabetes [6], Zavesca (N-butyldeoxynojirimycin, NBDNJ, 2), which is used for lysosomal storage disorders including Gaucher and Niemann–Pick type.

Methods

Results

Conclusion