Structure Based Drug Designing, Scoring, and Synthesis of Some Substituted Sulphonylureas/Guanidine -Based Derivatives as Hypoglycemic Agents

Abstract

Objective:The present work deals with the designing, scoring, synthesis and, characterization of 1-(4-(2-(4-Substitutedphenylamino)-2oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl)urea (5A-5B),1-(4-(2-(4-substitutedphenylamino)-2-oxoethyl)phenylsulfonyl)-3-(4-substitutedbenzoyl)guanidine(5C-5E) and, 1-(4-Substitutedbenzoyl)-3-(4-(2-oxo-2-(piperazin-1-yl)ethyl)phenylsulfonyl)urea (5F-5H) based derivatives as hypoglycemic agents.Methods: Docking calculations were performed to predict the binding affinity between the AKR1C1 complexes and sulphonylureas compounds using the Glide docking program. Docking studies on LigPrep treated ligands were carried out to predict the binding pocket of protein 4YVP using the docking program. The QikProp program was used to predict the ADME/T properties of the analogues. All these newly synthesized compounds were screened for their in vivo hypoglycemic activity by most relevant animal models like alloxan-induced diabetic rats by measuring blood plasma concentration compared with reference drug glibenclamide.Results: Novel compounds 1were synthesised and characterized using spectral and analytical data. The results of molecular docking and in vivo hypoglycemic activity, all compounds have shown considerable activity with respect to glibenclimide, but compounds 5D (52.49±7.73) and 5E(48.18±4.22)are equipotent with respect to activity as compared to standard glibenclamide(55.97±3.19). Conclusion:Compounds 5D and 5E have exhibited good hypoglycemic activity,hence both the derivatives will consider as a lead molecule and further some modification in their structures to get a more potent anti-diabetic agent.Group I: Normal-Normal controlled rats fed with 0.5 ml of normal saline.Group II: Diabetic control (DC) rats; fed with 0.5 ml of normal saline.Group III: Diabetic rats treated with standard drug Glibenclamide 5 mg/kg body wt. Group IV: Diabetic rats; treated with synthesized drug No 5A in 1% CMC 50 mg/kg of body weight. Group V: Diabetic rats; treated with synthesized drug No 5B in 1% CMC 50 mg/kg of body weight Group VI: Diabetic rats; treated with synthesized drug No 5C in 1% CMC 50 mg/kg of body weight Group VII: Diabetic rats; treated with synthesized drug No 5D in 1% CMC 50 mg/kg of body weight Group VIII: Diabetic rats; treated with synthesized drug No 5E in 1% CMC 50 mg/kg of body weight Group IX: Diabetic rats; treated with synthesized drug No 5F in 1% CMC 50 mg/kg of body weight Group X: Diabetic rats; treated with synthesized drug No 5G in 1% CMC 50 mg/kg of body weight Group XI: Diabetic rats; treated with synthesized drug No 5H in 1% CMC 50 mg/kg of bodyThe dose for the newly synthesized compounds was decided on the basis of literature survey. [29] Glibenclamide was taken as the standard. The blood glucose level was determined at 0 and 3 h after administration of test compound using glucometer (Johnson and Johnson Pvt. Ltd.) % reduction in plasma glucose level was calculated for each animal. Statistical analysisPanchal et al. Pharm Sci, Vol 9, Issue 12, 226-232 Int J Pharm

Synthesis and Evaluation of Antidiabetic Properties of a Zinc Mixed Ligand Complex in High-Fat Diet - Low-Dose Streptozotocin-Induced Diabetic Rats

“…Likewise, if the therapeutic dose of an oral hypoglycemic drug (OHD) could be partly reduced by replacing it with a biologically active phytochemical, the side effects caused by the former could be reduced to a greater extent [20]. However, the interactions between the OHD and the phytochemical in terms of stability, bioavailability, and metabolism have to be established for successful therapeutic strategies [21].…”

Effect of Perillyl Alcohol (POH) A Monoterpene on Lipid Peroxidation and Antioxidant Status in High Fat Diet-Low Dose STZ Induced Type 2 Diabetes in Experimental Rats

“…33 However, the interactions between the oral hypoglycemic drugs and the phytochemical in terms of stability, bioavailability, and metabolism have to be established for successful therapeutic strategies. 34 High Fat Diet induced Oxidative stress is engaged in the development of diabetes and also its later complications are well mimicked by the diabetogenic action of STZ administration and also lead to chronic hyperglycemia. GSH for plasma and tissues were expressed as mg/dl and µg/mg protein.…”

Hepatoprotective Effect of Perillyl Alcohol (Poh) on High-Fat Diet-Low-Dose Streptozotocin-Induced Type 2 Diabetes in Experimental Rats

“…Presently available drug regimens in the market for the management of DM have certain side effects so there is a need to find safer and more effective antidiabetic drugs with no or very less side effects especially from plant origin [19]. For the successful therapeutic strategies, we need to have interaction between the oral hypoglycemic drugs and the phytochemicals in terms of bioavailability, metabolism, and steadiness [20]. The present study was meant to determine the efficiency of perillyl alcohol on hepatoprotective activity of normal and HFD-STZinduced diabetic rats.…”