RESUMO
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.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores Enzimáticos/química , Furanos/química , Piranos/química , Tirosina-tRNA Ligase/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Furanos/farmacologia , Conformação Molecular , Estrutura Molecular , Staphylococcus aureus/enzimologia , Staphylococcus aureus/metabolismoRESUMO
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.
