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Artículo

Evaluation and synthesis of AZT prodrugs with optimized chemical stabilities: Experimental and theoretical analyses

Ribone, Sergio RomanIcon ; Schenfeld, Esteban MartinIcon ; Madrid, Marcela; Pierini, Adriana BeatrizIcon ; Quevedo, Mario AlfredoIcon
Fecha de publicación: 01/2016
Editorial: Royal Society of Chemistry
Revista: New Journal of Chemistry
ISSN: 1144-0546
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Otras Ciencias Químicas

Resumen

The design of prodrugs of nucleoside reverse transcriptase inhibitors (NRTIs) constitutes a promising strategy to overcome several suboptimal pharmacotherapeutic properties of these kinds of drugs, among which zidovudine (AZT) is the most studied example. The chemical stability of prodrugs is a critical issue in the context of their pharmacotherapeutic performance since it constitutes a key event in the reconversion of the bioactive NRTIs. In this study, five prodrugs of AZT and lamivudine (3TC) were studied by means of DFT and classical molecular dynamics (MD) strategies in order to model the reaction coordinates involved in their chemical hydrolysis, and extend these conclusions to further structure rationalization of prodrugs. Therefore, the inclusion of explicit water molecules was found to be of great relevance to the mentioned reaction coordinates since it allowed a very good correlation between calculated reaction energy values and the corresponding hydrolysis constants. Based on these findings, three ester based prodrugs of AZT were designed, synthesized and evaluated regarding their chemical stability. These prodrugs exhibited optimized chemical stabilities when compared to the previously reported AZT prodrugs, which may result in an enhanced pharmacotherapeutic performance. In conclusion, the developed theoretical model provides a valuable assistance in the design and development of novel prodrugs of NTRIs with rationalized chemical stabilities.
Palabras clave: Prodrugs , Quantum Calculations , Chemical Stability
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/62948
DOI: http://dx.doi.org/10.1039/c5nj03002a
URL: https://pubs.rsc.org/en/Content/ArticleLanding/2016/NJ/C5NJ03002A
Colecciones
Articulos(UNITEFA)
Articulos de UNIDAD DE INVESTIGACION Y DESARROLLO EN TECNOLOGIA FARMACEUTICA
Citación
Ribone, Sergio Roman; Schenfeld, Esteban Martin; Madrid, Marcela; Pierini, Adriana Beatriz; Quevedo, Mario Alfredo; Evaluation and synthesis of AZT prodrugs with optimized chemical stabilities: Experimental and theoretical analyses; Royal Society of Chemistry; New Journal of Chemistry; 40; 3; 1-2016; 2383-2392
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