S-acyl-2-thioethyl aryl phosphotriester derivatives of AZT: Synthesis, antiviral activity, and stability study

Abstract

The synthesis, antiviral activity, and stability study of phosphotriester derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT) bearing modified L-tyrosinyl residues are reported. These compounds were obtained via phosphoramidite (PIII) chemistry from the appropriate aryl precursors. All the derivatives were evaluated for their in vitro anti-HIV activity, and they appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments, with EC50 values between the micro- and nanomolar range, especially in thymidine kinase deficient (TK-) cells, showing their ability to act as mononucleotide prodrugs. The proposed decomposition process of these mixed mononucleoside aryl phosphotriesters successively involves an esterase and a phosphodiesterase hydrolysis.