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) << AZT-Suc (stable) < AZT-Glu (stable) < AZT-Adi (stable). Under basic conditions (pH=10) the hydrolysis rate is considerably higher: AZT-Ox (10.9 min) << AZT-Adi (6.8 hs) < AZT-Glu (7.7 hs) < AZT-Suc (10.5 hs). In both conditions, marked stability differences were observed for AZT-Ox when compared to the rest of the prodrugs. Theoretical findings: Applying molecular dynamics simulations it was observed that the carboxylate moieties and carbonyl oxygens of the ester functions establishes stable hydrogen bond interactions with solvent (water) molecules. This feature reduces the energetic barrier for the nucleophilic attack of the hydroxyl group to the ester under basic conditions. This effect is maximum for AZT-Ox, and is considerably lower for the rest of the prodrugs analyzed (consistent with experimental findings). From the above results, it can be concluded that the rate of hydrolysis of the studied prodrugs is dependent on the solvation shell surrounding the carboxylate moiety. Detailed molecular modeling techniques are able to account for the interplay between solvation and conformational properties, providing a powerful tool for the design of 5? OH prodrugs with rationalized reconversion rates.