SYNTHESIS OF PYRIDAZINE ACETIC-ACID DERIVATIVES POSSESSING ALDOSE REDUCTASE INHIBITORY ACTIVITY AND ANTIOXIDANT PROPERTIES

N-Acetic acid derivatives of 4-carboxy-6-arylpyridazin-3-ones were syn thesized for the dual purpose of inhibiting aldose reductase and exhib iting antioxidant properties. All the prepared compounds showed a sign ificant in vitro aldose reductase inhibitory effect (10(-5) M less tha n or equal to IC50 less than or equal to 10(-4) M). The spatial config uration of the most active derivative 4f (4-i-PrC6H4 at C-6, IC50 = 0 95 x 10(-5) M) was compared with pharmacophore requirements of the ald ose reductase inhibitor site using a molecular modeling system. The an tioxidant action of 4a-f was also studied in vitro. Compound 4c (4-ClC 6H4 at C-6, IC50 = 1.56 x 10(-3) M) was the most effective at scavengi ng the superoxide anion whereas compound 4a (C6H5 at C-6, IC50 = 1.28 x 10(-3) M) was the most active at inhibiting lipid peroxidation. In a ddition, biological activities (log 1/IC50) for most of the data sets could be correlated directly to lipophilic, electronic and steric para meters.