ABSTRACT
N-Alkyl and N,N-dialkyl derivatives of 2-amino-2-deoxy-d-glucitol-6P (ADGP) were synthesized and found to inhibit growth of human pathogenic fungi (MICs in the 0.08-0.625mgmL(-1) range for the most active compounds). It was thus shown that N-alkylation of ADGP provides novel inhibitors of a fungal enzyme, glucosamine-6P synthase, exhibiting higher antifungal activity than the parent compound, due to the increased lipophilicity and better uptake by fungal cells.
Subject(s)
Antifungal Agents/chemical synthesis , Glucosamine/analogs & derivatives , Antifungal Agents/pharmacology , Candida albicans/drug effects , Candida albicans/enzymology , Candida albicans/growth & development , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glucosamine/chemical synthesis , Glucosamine/pharmacology , Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/antagonists & inhibitors , Humans , Microbial Sensitivity Tests , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/growth & developmentABSTRACT
Mono- and di-N-alkylated derivatives of 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-beta-D-glucose (alkyl=methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl) were synthesised by the reductive alkylation of per-O-acetyl-d-glucosamine. (N-ethyl, N-propyl, N-butyl, N-pentyl and N-hexyl)-1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-beta-D-glucoses were deacetylated in order to attempt an enzymatic phosphorylation. All products were characterised by means of IR, NMR and MS spectra. N-Ethyl- and N-pentyl-d-glucosamines were found to exhibit weak antifungal activity.
Subject(s)
Deoxyglucose/chemistry , Glucosamine/analogs & derivatives , Antifungal Agents/pharmacology , Carbohydrate Conformation , Carbohydrate Sequence , Deoxyglucose/chemical synthesis , Glucosamine/chemical synthesis , Glucosamine/chemistry , Glucosamine/pharmacology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Chemical , Molecular Sequence Data , Phosphorylation , Protons , Spectrophotometry, Infrared , TemperatureABSTRACT
The single-crystal X-ray diffraction and high-resolution 1H and 13C NMR spectral data for the title compound are reported. The influence of the ring oxygen atom on the J(1,2e) and J(4,5) coupling constants for 2-deoxy-D-lyxo- and -D-xylo-hexopyranosides is discussed.
