RESUMO
In the course of our search for selective iNOS inhibitors, we have previously reported that 2-imino-1,3-oxazolidine derivatives (1) and 2-aminothiazole derivatives (2) are selective iNOS inhibitors. In order to find more potent iNOS inhibitors, we focused our efforts on the synthesis and evaluation of the inhibitory activity against iNOS and selectivity for iNOS both in vitro and in vivo of a series of 2-imino-1,3-thiazolidine derivatives (3), which are analogues of 1 and 2. Our results show that among the compounds synthesized (4R,5R)-5-ethyl-2-imino-4-methyl-1,3-thiazolidine [(4R,5R)-14a: ES-1537] exhibited potent inhibitory activity and selectivity for iNOS. In addition, ES-1537 had good pharmacokinetic profile in rats with BA value of 80%. It is therefore expected that ES-1537 may be therapeutically useful for the treatment of diseases related to excess production of NO.
Assuntos
Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Linhagem Celular , Inibidores Enzimáticos/síntese química , Feminino , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico Sintase/sangue , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II , Ratos , Ratos Wistar , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
In this study, we report the design, synthesis and structure-activity relationships of novel indazole derivatives as DNA gyrase inhibitors with Gram-positive antibacterial activity. Our results show that selected compounds from this series exhibit potent antibacterial activity against Gram-positive bacteria including multi-drug resistant strains that is methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE).