Chemical hydrolysis of zidovudine prodrugs: correlation between experimental and theoretical studies

SCHENFELD, E.M.; RIBONE, S.R.; PIERINI, A.; QUEVEDO, M.A.

Córdoba

Congreso; 3a. Reunión Internacional de Ciencias Farmacéuticas; 2014

Dpto. Farmacia - Fac. Ciencias Químicas - UNC

The design of prodrugs of zidovudine (AZT) allows the optimization of its pharmacotherapeutic properties, among which acidic prodrugs encompasses the main potential to reach optimized biodistributions. Considering that an adequate chemical stability constitutes a critical property of a prodrug, in this work we present a structure-stability relationship for a serie of AZT prodrugs obtained by esterification of the 5?-OH with the following organic diacids: oxalic (AZT-Ox), succinic (AZT-Suc), glutaric (AZT-Glu) and adipic (AZT-Adi). A relationship between experimental assays and state of the art molecular modeling techniques is established. Experimental findings: the rate of chemical hydrolysis of AZT prodrugs is highly dependent on the pH and molecular structure involved. Half-life times (t1/2) under acidic conditions (pH=2) are: AZT-Ox (21.2 hs)