RESUMO
Molecular design, synthesis, in vitro and in vivo studies of novel derivatives of indole-3-carboxylic acid new series of angiotensin II receptor 1 antagonists is presented. Radioligand binding studies using [125I]-angiotensin II displayed that new derivatives of indole-3-carboxylic acid have a high nanomolar affinity for the angiotensin II receptor (AT1 subtype) on a par with the known pharmaceuticals such as losartan. Biological studies of synthesized compounds in spontaneously hypertensive rats have demonstrated that compounds can lower blood pressure when administered orally. Maximum the decrease in blood pressure was 48 mm Hg with oral administration of 10 mg/kg and antihypertensive effect was observed for 24 h, which is superior to losartan.
Assuntos
Anti-Hipertensivos , Hipertensão , Ratos , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Losartan/farmacologia , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/química , Antagonistas de Receptores de Angiotensina/farmacologia , Pressão Sanguínea , Ratos Endogâmicos SHR , Receptores de Angiotensina/metabolismo , Angiotensina II/farmacologia , Tetrazóis/química , Compostos de Bifenilo/químicaRESUMO
We herein report new 5-substituted uridine derivatives as potent inhibitors of mycobacteria - causative agents of tuberculosis. A series of new 5-alkynyl-substituted uridine derivatives were synthesised via palladium-catalysed Sonogashira cross-coupling reaction of 5-iodo-6-methylpyrimidine base with terminal acetylenes with good yields in DMF at room temperature. It was found that methyl group in C-6 position of pyrimidine ring had no impact on yields of target compounds. All obtained compounds were evaluated for their antimycobacterial activity against Mycobacetrium bovis and Mycobacterium tuberculosis at concentrations of 1-100 µg/ml using MABA test. Synthesized nucleosides showed high antimycobacterial activity against M. bovis and M. Tuberculosis. The MIC50 values of 11 and 13 were similar or close to that of the reference drug rifampicin.
Assuntos
Antituberculosos/farmacologia , Desenho de Fármacos , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Nucleosídeos de Pirimidina/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/química , Relação Estrutura-AtividadeRESUMO
A series of new 5-alkynyl-substituted uracil and uridine derivatives were synthesised via palladium-catalysed Sonogashira cross-coupling reaction of 5-bromo-pyrimidine base with terminal acetylenes with good yields in DMF at room temperature. All obtained compounds were tested for antimycobacterial activity against Mycobacetrium bovis and Mycobacterium tuberculosis (H37Ra) at concentrations of 1-100 µg/ml using MABA test. Obtained results revealed that most of tested uracil derivatives exhibited high antimycobacterial activity (MIC50 = 1.1-19.2 µg/ml) in comparison with therapeutic agents such as rifampicin, isoniazid and d-cycloserine, excluding compounds having alkyl substituent at triple alkyne bond.