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

Abstract

Amino acid and dipeptide esters of metronidazole were synthes!zed and evaluated on their hydrolytic stability in various buffers and culture media. The hydrol ic susceptibility of the different esters was minimal in the pH range 3 -5: In the alkaline region, pH 6,5 -$'the halflifes were of the order of 1 -6.6 hrs. At alkaline H the di eptide esters were more susceptible towards hydrol sis. At pH 8.8 the observed half-life for the gg-gly ancfthe gly-phe esters was 0.2 h, whereas for the ly and t ! e phe ester it was 1.1 h, respectively 2.7 h. It was demonstrated that the increased rate of hydrobsis for the dipeptide esters was due to an intramolecular aminolysis with the formation of a diketopiperazine accompanied by the release of free metronidazole. INTRODUCTIONMetronidazole (I) is widely used for the treatment of certain anaerobic infections. At present it is available in oral dosage forms. In order to extent its use to parenteral administration low molecular as well as macr~molecular~~~ prodrugs have been prepared. Amino acid esters of metronidazole (11) have been described by Bundgaardl and by Cho2. The rate of hydrolysis of these amino acid esters in buffers of various pH was reported.As part of a project on the synthesis and evaluation of water soluble prodrugs of metronidazole' we have prepared dipeptide esters (111) of the parent drug and investigated their hydrolytic stability in comparison with a number of amino acid ester derivatives.