Synthesis and glycosidase inhibitory profiles of functionalised morpholines and oxazepanes
Burland, P. A., Osborn, H. M. I. and Turkson, A. (2011) Synthesis and glycosidase inhibitory profiles of functionalised morpholines and oxazepanes. Bioorganic & Medicinal Chemistry, 19 (18). pp. 5679-5692. ISSN 0968-0896
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To link to this article DOI: 10.1016/j.bmc.2011.07.019
In this work libraries of morpholines and oxazepanes have been prepared via the reductive amination reaction between dialdehydes, derived from carbohydrates, and a range of amines. In this way, functionalised morpholines and oxazepanes have been prepared that include N-alkylated derivatives, disaccharide analogues, and ester containing derivatives. The abilities of these functionalised morpholines and oxazepanes to inhibit a broad panel of glycosidase enzymes, that are associated with a range of diseases, have been probed and in this way new inhibitors of a range of glycosidases, but particularly β-d-galactosidase derived from Bovine kidney, have been discovered. N-Alkyl morpholines demonstrated the best inhibition profiles for this enzyme and derivatives (15a)–(15d) acted as non-competitive inhibitors with IC50 values of 55.1–88.6 μM. Within this study, some preliminary structure–activity relationships are proposed, and it is demonstrated that N-substituted morpholines display better inhibitory profiles for the enzymes analysed than any of the N-substituted oxazepanes.