title: Synthesis and glycosidase inhibitory profiles of functionalised morpholines and oxazepanes.
abstract: 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 IC(50) 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.
authors.affiliation: Reading School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Burland
authors.forename: Helen M I
authors.initials: HM
authors.lastname: Osborn
authors.forename: Andrea
authors.initials: A
authors.lastname: Turkson
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010077:Oxazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009025:Morpholines; D010077:Oxazepines; D054852:Small Molecule Libraries; D006026:Glycoside Hydrolases