ABSTRACT
Novel pyranosyl analogues of SB-219383 have been synthesised to elucidate the structure-activity relationships around the pyran ring. Analogues with highly potent stereoselective and bacterioselective inhibition of bacterial tyrosyl tRNA synthetase have been identified. A major reduction in the overall polarity of the molecule can be tolerated without loss of the nanomolar level of inhibition.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Enzyme Inhibitors/chemistry , Furans/chemistry , Pyrans/chemistry , Tyrosine-tRNA Ligase/antagonists & inhibitors , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Furans/pharmacology , Molecular Conformation , Molecular Structure , Staphylococcus aureus/enzymology , Staphylococcus aureus/metabolismABSTRACT
Synthetic analogues of the microbial metabolite SB-219383 have been synthesised with defined stereochemistry. Densely functionalised hydroxylamine containing amino acids were prepared by the addition of a glycine anion equivalent to sugar-derived cyclic nitrones. One of four stereoisomeric dipeptides incorporating these novel amino acids was found to be a potent and selective inhibitor of bacterial tyrosyl tRNA synthetase, suggesting analogous stereochemistry of the natural product.
