Design and synthesis of pyridazinone-substituted benzenesulphonylurea derivatives as anti-hyperglycaemic agents and inhibitors of aldose reductase - an enzyme embroiled in diabetic complications.

Thirty new aryl-pyridazinone-substituted benzenesulphonylurea derivatives (I-XXX) were synthesized and evaluated for their anti-hyperglycaemic activity in glucose-fed hyperglycaemic normal rats. Twenty-three compounds (III-XI, XIV-XVII, XIX-XXIV, XXVI and XXVIII-XXX) showed more or comparable area under the curve (AUC) reduction percentage (ranging from 21.9% to 35.5%) as compared to the standard drug gliclazide (22.0%). On the basis of docking results, 18 compounds were screened for their in vitro ability to inhibit rat lens aldose reductase. Ten compounds (III-VI, XII, XVI-XVIII, XXI and XXVII) showed ARI activity with IC50 ranging from 34 to 242 μM. Out of these, two compounds IV and V showed best ARI activity which is comparable with that of quercetin. As a result, two compounds (IV and V) possessing significant dual action (anti-hyperglycaemic and aldose reductase inhibition) were identified and may be used as lead compounds for developing new drugs.