Side-chain effects on solubility, chemical stability, and bioactivation of propofol ester prodrugs

Propofol is a widely used intravenous anesthetic, but its extremely low aqueous solubility requires lipid-based formulations associated with pharmaceutical limitations. This study aimed to investigate how side-chain structure influences the aqueous solubility, chemical stability, and esterase-mediated bioactivation of propofol ester prodrugs. Thirteen amino acid and dicarboxylate ester derivatives of propofol were synthesized and evaluated for aqueous solubility, chemical stability in phosphate buffer, and metabolic conversion in 50 % human plasma and human liver microsomes (HLM). Selected compounds were further examined by inhibitor studies and time-dependent NMR analysis. All prodrugs exhibited markedly improved aqueous solubility compared with propofol, and five derivatives exhibited propofol-equivalent solubilities exceeding the practical benchmark of 10 mg/mL used in this study. Most compounds remained chemically stable in phosphate buffer at pH 7.0, whereas succinate-, aspartate-, and γ-aminobutyric acid-derived esters showed partial non-enzymatic degradation. Time-dependent NMR analysis suggested that the instability of the succinate derivative was associated with intramolecular cyclization. Distinct side-chain-dependent differences were also observed in esterase-mediated activation. Valine- and γ-aminobutyric acid-derived esters underwent relatively rapid conversion in human plasma, whereas the phenylalanine derivative showed the highest metabolic conversion in HLM. Hydrolysis of the phenylalanine ester in HLM was strongly inhibited by bis-p-nitrophenyl phosphate (BNPP), indicating substantial involvement of carboxylesterases in the activation process. These results demonstrate that side-chain structure strongly influences the balance among aqueous solubility, chemical stability, and esterase-mediated bioactivation of propofol ester prodrugs. The present study provides useful structure-property relationships for the design and evaluation of water-soluble ester prodrugs.