Design, synthesis, and pharmacological evaluation of the aqueous prodrugs of desmethyl anethole trithione with hepatoprotective activity.

Abstract A metabolite-based prodrug strategy to increase the solubility of anethole trithione was reported to facilitate the clinical application of this hepatoprotective agent. Water-soluble analogs of anethole trithione were synthesized via substituting the methyl group of anethole trithione with the simple hydrophilic alkylamino group, and subjected to physiochemical, pharmacological and metabolic studies. The prodrugs displayed increased solubility as well as other physiochemical properties favorable for parenteral use. Among the analogs synthesized, the compound 5a exhibited best hepatoprotective activity at the dose of 2.0 mg/kg in mice equal to that of anethole trithione. The in vivo metabolic investigation demonstrated that the straight-side chain prodrug 5a could convert to desmethyl anethole trithione in vivo, while the ring-side chain prodrug 5d could not. The hepatoprotective activity of the prodrugs might result from the active metabolite desmethyl anethole trithione.