Prodrugs of acyclovir--a computational approach.

Density functional theory calculation results demonstrated that the efficiency of the acid-catalyzed hydrolysis of Kirby's acid amides 1-15 is strongly dependent on the substitution on the C-C double bond and the nature of the amide N-alkyl group. Further, the results established that while in the gas phase the hydrolysis rate-limiting step is the tetrahedral intermediate formation in polar solvents such as water, the rate-limiting step could be either the formation or the collapse of the tetrahedral intermediate depending on the substitution on the C-C double bond and on the amide nitrogen substituent. Based on a linear correlation between the calculated and experimental effective molarities, the study on the systems reported herein could provide a good basis for designing prodrug systems that are less hydrophilic than their parental drugs and can be used, in different dosage forms, to release the parent drug in a controlled manner. For example, based on the calculated log effective molarities values, the predicted t(1/2) (a time needed for 50% of the reactant to be hydrolyzed to products) for acyclovir prodrugs, ProD 1-4, was 29.2 h, 6097 days, 4.6 min, and 8.34 h, respectively. Hence, the rate by which acyclovir prodrug releases acyclovir can be determined according to the structural features of the linker (Kirby's acid amide moiety).
(© 2012 John Wiley & Sons A/S.)