Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/21171
Título: Lipophilic pyrazinoic acid amide and ester prodrugs Stability, activation and activity against M. tuberculosis
Autor: Simoes, Marta Filipa
Valente, Emilia
Rodriguez Gomez, M. Jose
Anes, Elsa
Constantino, Luis
Palavras-chave: Pharmacology & Pharmacy
Data: 2009
Editora: ELSEVIER SCIENCE BV
Citação: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES. - Vol. 37, n. 40271 (2009), p. 257-263
Resumo: Pyrazinamide (PZA) is active against M. tuberculosis and is a first line agent for the treatment of human tuberculosis. PZA is itself a prodrug that requires activation by a pyrazinamidase to form its active metabolite pyrazinoic acid (POA). Since the specificity of cleavage is dependent on a single bacterial enzyme, resistance to PZA is often found in tuberculosis patients. Esters of POA have been proposed in the past as alternatives to PZA however the most promising compounds were rapidly degraded in the presence of serum. In order to obtain compounds that could survive during the transport phase. we synthesized lipophilic ester and amide POA derivatives, studied their activity against M. tuberculosis, their stability in plasma and rat liver homogenate and also their activation by a mycobacterial homogenate. The new lipophilic ester prodrugs were found to be active in concentrations 10-fold lower than those needed for PZA to kill sensitive M. tuberculosis and also have a Suitable stability in the presence of plasma. Amides of POA although more stable in plasma have lower activity. The reason can probably be found in the rate of activation of both types of prodrugs: while esters are easily activated by mycobacterial esterases, amides are resistant to activation and are not transformed into POA at a suitable rate. (C) 2009 Elsevier B.V. All rights reserved.. - iMed ; ADEIM ; FCT [POCI/BIA-BCM/55327/2004]. - We thank Dr. Bernard Testa for valuable suggestions and review of the manuscript and Dr. Jorge Vitor for his helpful advice on preparing the mycobacterial homogenate. Our work was supported by iMed, ADEIM and by FCT grant POCI/BIA-BCM/55327/2004.
URI: http://hdl.handle.net/10451/21171
DOI: http://dx.doi.org/10.1016/j.ejps.2009.02.012
ISSN: 0928-0987
Aparece nas colecções:FF - Produção Científica 2000-2009

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