Design and synthesis of novel bis(l-amino acid) ester prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) with improved anti-HBV activity

A series of novel bis(l-amino acid) ester prodrugs of 9-[2-(phosphonomethoxy)ethyl] adenine (PMEA) was synthesized and their anti-HBV activity was evaluated in HepG 2 2.2.15 cells. Compounds 11, 12, 21, 22, 26, and 27 demonstrated more potent anti-HBV activity and higher selective index (SI) than adefovir dipivoxil, which was used as a positive control. Compound 11, which was found to be the most potent one, was five times more potent than adefovir dipivoxil with EC50 value of 0.095 μM and CC50 value of 6636 μM. The SI value (>69,000) of compound 11 was 60 times and 24 times higher than those of adefovir dipivoxil and lamivudine, respectively. In vitro stability studies showed that compound 11 was relatively more stable than adefovir dipivoxil with t1/2 of 270 min. These findings suggested that compound 11 could be considered as a promising candidate for further in vivo studies.

Graphical abstractA series of novel bis(l-amino acid)ester prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 11 exhibited five times more potent anti-HBV activity, 60 times higher selective index (SI) than adefovir dipivoxil. Moreover, compound 11 was more stable than adefovir dipivoxil with t1/2 of 270 min.Figure optionsDownload full-size imageDownload as PowerPoint slide