Niridazole prodrugs: Synthesis, characterization and hydrolysis kinetics of some N-acyloxymethyl niridazoles

ABSTRACT

A series of 3-acyloxymethylniridazole have been prepared by acylation of 3-hydroxymethylniridazole. The structure of the prepared compounds was confirmed by IR, 1 H-NMR and elemental analysis. They were also evaluated with regard to water solubility, partition coefficient, hydrolysis kinetics and enzymatic cleavage. The water solubility of some of these prodrugs was markedly improved over that of niridazole. Meanwhile, their lipid solubility was comparable with that of the parent drug. In vitro chemical stability of all the synthesized prodrugs was studied at different pH-values, as well as in 80% human plasma for one of themas representative example to assess its cleavage enzymatically to the parent drug, in both cases a strict first- order hydrolysis kinetics was observed. The t 1/2 values varied with variation of the acyl-moiety. The obtained results show as significant improvement in physicochemical properties of the products relative to the parent drug