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

Abstract

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.