Synthesis, stability and pharmacological evaluation of a novel codrug consisting of lamivudine and ursolic acid

A novel codrug (LMX) was obtained from lamivudine (LMV) and ursolic acid (UA) coupled with ethyl chloroacetate through an amide and ester linkage. The structure of LMX was confirmed by 1H NMR, 13C NMR, IR and HRMS. Herein, the in vitro non-enzymatic and enzymatic hydrolysis and in vivo pharmacological activities of LMX were studied. The kinetics of hydrolysis of LMX was studied in aqueous solution of pH 1–10, 80% buffered human plasma and in the presence of lipase from Porcine pancreas (EC 3.1.1.3) at 37 °C. It is found that LMX hydrolysis rate was significantly faster in lipase with half-life of 1.4 h compared to pH 7.4 phosphate buffer (t1/2 11.2 h) and buffered human plasma (t1/2 5.4 h). The decomposition rates in aqueous solution (pH 1–10) showed a U-shaped curve. LMX was comparatively stable between pH 3 and 6 (half-life >40 h). Pharmacological studies indicated that LMX had the dual action of anti-hepatitis B virus activity and hepatoprotective effects against acute liver injury. These findings suggest that LMX could be a promising candidate agent for the treatment of hepatitis.

The synthesis, stability and pharmacological evaluation of a novel codrug LMX are reported.Figure optionsDownload as PowerPoint slide