VICENTE CONSTANTINO, Luis Filipe,RIBEIRO ANES, Elsa Maria,TORROAES VALENTE, Emília Alice,BAPTISTA DE ALMEIDA, Teresa Sofia,BALTAZAR DO CARMO, Nuno
申请号：
IBIB2012/057149
公开号：
WO2013/084214A2
申请日:
2012.12.10
申请国别(地区):
WO
年份:
2013
代理人:
摘要：
Since pyrazinamide is in fact a prodrug of pyrazinoic acid, other prodrugs of pyrazinoic acid, like esters, could have activity against M. tuberculosis. These compounds should be resistant to the human plasma and liver enzymes, but must be readily hydrolyzed, by mycobacteria, at the site of action. Esters were proposed in the past as prodrugs of pyrazinoic acid. The main advantage of those compounds is that they are not activated by a specific enzyme (pirazinamidase) but by a large array of esterases preventing the onset of resistance by this mechanism. However, these compounds must reach the mycobacteria in the prodrug form otherwise they cannot penetrate the mycobacterial wall and since plasma has also esterases the compounds studied were rapidly hydrolysed. Amide prodrugs are resistant to plasma hydrolysis however the compounds cannot be activated efficiently by mycobacterial esterases and do not present activity. New branched lipophilic esters were synthesized in order to delay their hydrolysis through the human plasma and liver before reaching the target mycobacteria. Their pseudo-first order rate constants for the hydrolysis in human plasma were evaluated as well as their activity against M. tuberculosis H37Ra. Branches in the first alkyl carbon, adjacent to the ester function, unexpectedly increased the stability and maintained the activity. The good stability of these compounds along with their activity against M. tuberculosis were the main achievements of this invention.Selon la présente invention, étant donné que le pyrazinamide est en fait un promédicament dacide pyrazinoïque, dautres promédicaments dacide pyrazinoïque, tels que des esters, pourraient avoir une activité contre M. tuberculosis. Ces composés doivent être résistants aux enzymes plasmatiques et hépatiques humaines, mais doivent être aisément hydrolysés, par des mycobactéries, au site daction. Des esters ont été proposés dans le passé en tant que promédicaments dacide pyrazinoïque. Le principa
