DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF GLYCOGEN SYNTHASE KINASE-3β INHIBITORS AS ANTIDIABETIC AGENTS

1. To synthesize structurally modified novel Glycogen Synthase Kinase-3βinhibitors to overcome insulin resistance in type 2 diabetes mellitus and to overcome associated health problems with reducing morbidity, mortality and economic costs of diabetes. Methods. Nineteen Phenylmethylene hydantoin analogs were designed and docked in the ATP binding site of GSK-3β by Molegro Virtual Docker 2006.1.5. The synthesis of proposed six hydantoin analogs were performed based on docking results by two approaches, Knoevenagel condensationand Steglich Esterification reaction, keeping the hydantoin ring and different ester substitution at benzylidene ring system can afford potent and selective GSK-3β inhibitors involved in the control of glycogen metabolism. The antidiabetic activity and liver glycogen content were also determined against Streptozotocin induced diabetic rat model. Results. The synthesized compounds H-a, H-c and  H-e increased hepatic glycogen content in range 410-420 mg/gm liver weight while compounds H-b, H-d and H-f cause increased in hepatic glycogen content in range of 357-370 mg/gm liver weight as compared to control having 242.01 mg/gm liver weight. Conclusion. The synthesized compounds decreased blood glucose level in glucose loaded hyperglycemia rats and also increased liver glycogen content. Structure activity relationship revealed that -ortho & -para chloro (electron withdrawing) substituted analogs favours for the activity while electron releasing (-methyl) substituted analogs having low potency.