Synthesis of Dipeptide Esters of Metronidazole and Evaluation of Their Hydrolytic Stability

Abstract

Amino acid and dipeptide esters of metronidazole were synthesized and evaluated on their hydrolytic stability in various buffers and culture media. The hydrolytic susceptibility of the different esters was minimal in the pH range 3 - 5. In the alkaline region, pH 6.5 - 8, the half-lifes were of the order of 1 - 6.6 hrs. At alkaline pH the dipeptide esters were more susceptible towards hydrolysis. At pH 8.8 the observed half-life for the gly-gly and the gly-phe esters was 0.2 h, whereas for the gly and the phe ester it was 1.1 h, respectively 2.7 h. It was demonstrated that the increased rate of hydrolysis for the dipeptide esters was due to an intramolecular aminolysis with the formation of a diketopiperazine accompanied by the release of free metronidazole.