• STUDY ON THE FIVE LEAD COMPOUNDS OF INHIBITING POLYOLPATHWAY ENZYME SDH

Abstract

Diabetes Mellitus is a chronic health disorder. It is characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. One of the complications of Diabetes Mellitus results in activation of Polyol pathway. Activation of the Polyol pathway results in a decrease of reduced NADP+ and oxidized NAD+; these are necessary cofactors in redox reactions throughout the body. Aldose reductase and sorbitol dehydrogenase are the enzymes of Polyol pathway. Excessive activation of the Polyol pathway increases intracellular and extracellular sorbitol concentrations, increased concentrations of reactive oxygen species and decreased concentrations of nitric oxide and glutathione. Each of these imbalances can damage cells; in diabetes there are several acting together. Drug designing study was carried out concentrating on the enzymes aldose reductase and sorbitol dehydrogenase of Polyol pathway, the drugs selected showed interaction with aldose reductase but showed no interaction with sorbitol dehydrogenase. So the study was concentrated mainly with aldose reductase (rate limiting enzyme). From the results it was concluded that five lead compounds namely

• Metformine,
• 1-(4-methylphenyl)-1,3,5-triazaspiro[5-5]undeca-2,4-diene-2,4-diamine
• 1-(4-flurophenyl)-1,3,5-triazaspiro[5-5]undeca-2,4-diene-2,4-diamine
• 1-(4-chlorophenyl)sulfonyl-3-(3 methylbutyl)urea

• 1-[4-[2-(cyclopropylmethoxy) ethyl] phenoxy]-3-(isopropyl amino) propan-2-ol showed interaction with the enzyme aldose reductase of Polyol pathway also when their SNP (single nucleotide polymorphism) amino acids were mutated so these compounds were selected as lead compounds from which effective drugs could be built and can be used to restrict the activation of the pathway confirmed with PreADMET analysis.