Fig. 1

In vitro cytotoxicity and in vivo pharmacokinetic analyses of BCV and the candidate compounds. a The molecular structures and the theoretical metabolic pathways of BCV and the newly synthesized prodrugs. After two steps of hydrolysis, BCV formate can be converted to the same active parent drug (CDV) with BCV. ODE-(S)-HPMPA formate and HDP-(S)-HPMPA formate also take two steps of hydrolysis to turn into (S)-HPMPA. b Comparisons of cytotoxicities between candidate compounds and BCV. Limited by the solubility of BCV formate, ODE-(S)-HPMPA formate and HDP-(S)-HPMPA formate, the highest concentration employed in the cytotoxicity assay was 40 μM. Data are presented as mean ± SD. c Comparisons of mitochondrial toxicity between candidate compounds and BCV. The solvent and CCCP served as negative and positive control, respectively. d, e Plasma concentrations of BCV, BCV formate, ODE-(S)-HPMPA formate and HDP-(S)-HPMPA formate, as well as their respective one-step hydrolytic metabolites CDV, BCV, ODE-(S)-HPMPA and HDP-(S)-HPMPA, were measured at various time points following a single oral gavage dose (3 mice per group, the mice were administered 10 ml/kg of each prodrug at a concentration of 7.12 µmol/ml). f, g Plasma concentrations of BCV, ODE-(S)-HPMPA, and HDP-(S)-HPMPA, as well as their hydrolytic metabolites (CDV and (S)-HPMPA) were measured at various time points following a single oral gavage dose (3 mice per group, the mice were administered 10 ml/kg of each prodrug at a concentration of 7.12 µmol/ml). Data are presented as mean ± SD. Statistical significance is indicated as follows: *p < 0.05; **p < 0.01; ****p < 0.0001