RESUMO
SB-203207 and 10 analogues have been prepared, by elaboration of altemicidin, and evaluated as inhibitors of isoleucyl, leucyl and valyl tRNA synthetases (IRS, LRS, and VRS, respectively). Substituting the isoleucine residue of SB-203207 with leucine and valine increased the potency of inhibition of LRS and VRS, respectively. The leucine derivative showed low level antibacterial activity, while several of the compounds inhibited IRS from Staphylococcus aureus WCUH29 more strongly than rat liver IRS.
Assuntos
Antibacterianos/síntese química , Inibidores Enzimáticos/síntese química , Indenos/química , Indenos/síntese química , Isoleucina-tRNA Ligase/antagonistas & inibidores , Piridinas , Sulfonamidas/química , Sulfonamidas/síntese química , Compostos de Enxofre , Valina-tRNA Ligase/antagonistas & inibidores , Alcaloides/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Indenos/farmacologia , Cinética , Fígado/enzimologia , Testes de Sensibilidade Microbiana , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
Aminoalkyl adenylates and aminoacyl sulfamates derived from arginine, histidine and threonine, have been prepared and tested as inhibitors of their cognate Staphylococcus aureus aminoacyl tRNA synthetases. The arginyl derivatives were both potent nanomolar inhibitors of the Class I arginyl tRNA synthetase whereas for the Class II histidyl and threonyl tRNA synthetases, the acyl sulfamates were potent inhibitors but the adenylates had very little affinity.
Assuntos
Monofosfato de Adenosina/análogos & derivados , Aminoacil-tRNA Sintetases/antagonistas & inibidores , Aminoacil-tRNA Sintetases/metabolismo , Inibidores Enzimáticos/síntese química , Staphylococcus aureus/enzimologia , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Monofosfato de Adenosina/síntese química , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Inibidores Enzimáticos/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
This paper describes the design and characterization of novel inhibitors of IleRS, whose binding affinity approaches the tightest reported for noncovalent inhibition. Compounds were designed from a binding model for the natural product pseudomonic acid-A (PS-A) together with a detailed understanding of the reaction cycle of IleRS and characterization of the mode of binding of the reaction intermediate IleAMP. The interactions of the compounds with IleRS were characterized by inhibition of aminoacylation of tRNA or PP(i)/ATP exchange at supersaturating substrate concentration and by transient kinetics and calorimetry methods. A detailed understanding of the interaction of a comprehensive series of compounds with IleRS allowed the identification of key features and hence the design of exquisitely potent inhibitors. Predictions based on these results have been recently supported by a docking model based on the crystal structure of IleRS with PS-A [Silvian, L. F., Wang J. M., and Steitz T. A. (1999) Science 285 1074-1077].
Assuntos
Antibacterianos/química , Inibidores Enzimáticos/síntese química , Isoleucina-tRNA Ligase/antagonistas & inibidores , Isoleucina-tRNA Ligase/química , Modelos Moleculares , Mupirocina/química , Antibacterianos/metabolismo , Sítios de Ligação , Varredura Diferencial de Calorimetria , Dicroísmo Circular , Inibidores Enzimáticos/metabolismo , Estabilidade Enzimática , Isoleucina/química , Isoleucina/metabolismo , Isoleucina-tRNA Ligase/metabolismo , Cinética , Modelos Químicos , Mupirocina/metabolismo , Espectrometria de Fluorescência , Staphylococcus aureus/enzimologia , Relação Estrutura-Atividade , TermodinâmicaRESUMO
The synthesis, antibacterial activities, murine pharmacokinetic and infection model data for a range of aryl and heteroaryl ketone derivatives of monic acid (2a) are reported. The best results were found for the 3-furyl and 2-methoxy thiazol-5-yl analogues.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Mupirocina/análogos & derivados , Mupirocina/química , Animais , Antibacterianos/farmacocinética , Humanos , Cetonas/química , Masculino , Camundongos , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Mupirocina/farmacologia , Sepse/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
Erythromycin A oxime 11,12-carbonate (5a) and its oxime ethers 5b approximately 5p have been prepared and their antibacterial activities compared with those of erythromycin A (1) and its 11,12-carbonate 2. The oxime 5a and many of its oxime ether derivatives showed good activity in vitro against Gram-positive and the more permeable Gram-negative organisms, in some cases being even more active than the carbonate 2.
