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
SB-219383 is a naturally occurring antibiotic, which acts by inhibition of tyrosyl tRNA synthetase. Semi-synthetic derivatives of SB-219383 were prepared with the objective of elucidating the key features required for inhibition of tyrosyl tRNA synthetase in order to improve the antibacterial activity. Some ester and amide derivatives as well as monocyclic analogues exhibited sub-nanomolar inhibitory activity against tyrosyl tRNA synthetase.
