Synthesis of cyanoacetate derivatives of succinimides and their anti-diabetic potential

Abstract

In current era, the most prevailing and significant health issue is Diabetes Mellitus. Diabetes Mellitus is a disease of glucose metabolism described by the raised amount of blood glucose caused by relative or absolute deficiency of insulin. Such high blood sugar proceeds to the onset of complication of diabetes which latter damages the eyes, kidneys and CNS. Hyperglycemia indicates dangerous factor for causing of disease of microvascular and macrovascular tissues. A variety of drugs are used in the management of diabetes mellitus, for example, insulin, sulphonylureas, AGIs and TZDs. Looking to the chemical structures of available antidiabetic drugs, new and simple molecules can be designed, synthesized and can be tested for their efficacy in the treatment of diabetes. Based on the close structural resemblance with thiazolidinediones, we have designed and synthesized pyrrolidinediones and have explored their antidiabetic potentials. In our current research work, we have reported fifteen (15) cyanoacetate derivatives of succinimides. Majority of the synthesized compounds have reported here for the first time. All the compounds are synthesized in a single step trivial reaction procedure. In DPPH assay, the compounds were tested for antioxidant activity and UOM3, UOM2 and UOM1 showed highest results with IC50 value of 92.50, 114.22 and 147.81 µg/ml respectively. In ABTS assay compounds UOM1, UOM5 and UOM2 showed high potency with IC50 value of 65.69, .71.15 and 110.43 µg/ml respectively. All other compounds showed weak antioxidant potentials. In in vitro alpha glucosidase inhibition assay, compounds UOM15, UOM13, UOM 14 and UOM 12 showed potent inhibition of alpha glucosidase with IC50 values of 10.2, 10.4,11.7 and 11.9 µg/ml respectively against the standard drug acarbose. All other tested compounds showed moderate potential with IC50 value of 11.8 to 41.86 µg/ml respectively. In vitro alpha amylase inhibitionv assay compounds UOM15 andUOM14 displayed highest IC50 value of 13.2 and 15.10 respectively compared to the standard drug acarbose. Based on the initial in-vitro assays, four (4) compounds were selected for further testing in experimental animals. In acute toxicity study, the tested compounds were revealed safe in the mentioned strength. In alloxan triggered diabetic mice, compounds UOM15, UOM14 and UOM13 displayed highest reduction in average glucose level over a period of 21 days, i.e. 6.44, 5.98 and 5.82 mmole/L respectively. While UOM 12 (i.e. 3.1 mmole/L) showed moderate reduction in bood glucose level. There was no significant increase in the LFTs and serum creatinine of treated mice. Also, a good result was recorded in the oral glucose tolerance test of the tested compounds against the standard Glibenclamide drug.In lipid peroxidation best result was displayed by UOM15 followed by UOM14, UOM13 and UOM12 against the standard glibenclamide. The synthesized compounds (UOM1-UOM15) showed a strong inhibitory potential against glucosidase and amylase and the inhibitory effect was revealed from the calculated Vmax and Km values for glucosidase and amylase inhibition and these were determined using Michaelis-Menten kinetics and further confirmed from the Linewear-Burk plots for glucosidase and amylase . From the current investigation it is evident that compounds UOM15, UOM14 and UOM13 have been verified that these compounds have stronger in-vivo antidiabetic than other prepared compounds so further work should be carried out to assess and extend its role in DM management to the next steps of drug development.