Synthesis, Characterization and Screening of Some Novel 2-Methyl-N'-[(Z)-Substituted-Phenyl ethylidene] Imidazo [1, 2-A] Pyridine-3-Carbohydrazide Derivatives as DPP-IV Inhibitors for the Treatment of Type 2 Diabetes Mellitus

Background: One of the leading global metabolic diseases marked by insulin resistance and chronic hyperglycemia is type 2 diabetes mellitus (T2DM). Since the last decade, DPP-4 enzyme inhibition has proved to be a successful, safe, and well-established therapy for the treatment of T2DM. Objective: The present work reports the synthesis, characterization, and screening of some novel 2-methyl-N'-[(Z)-substituted-phenyl ethylidene] imidazo [1, 2-a] pyridine-3-carbohydrazide derivatives as DPP-IV inhibitors for the treatment of T2DM. Methods: The molecular docking was performed to study these derivatives' binding mode in the enzyme's allosteric site. All the synthesized compounds were subjected for DPP-IV enzyme assay and in vivo antihyperglycemic activity in STZ-induced diabetic rats. Results: The synthesized derivatives exhibited potent antidiabetic activity as compared to the standard drug Sitagliptin. Out of sixteen compounds, A1, A4, B4, C2, C3, and D4 have shown promising antidiabetic activity against the DPP-IV enzyme. The most promising compound, C2, showed a percentage inhibition of 72.02±0.27 at 50 µM concentration. On the 21st-day compound, C2 showed a significant reduction in serum blood glucose level, i.e., 156.16±4.87 mg/dL, then diabetic control, which was 280.00±13.29 mg/dL whereas, standard Sitagliptin showed 133.50±11.80 mg/dL. In the in vivo antihyperglycemic activity, the compounds have exhibited good hypoglycemic potential in fasting blood glucose in the T2DM animal model. All the docked molecules have exhibited perfect binding affinity towards the active pocket of the enzyme. The synthesized derivatives were screened through Lipinski's rule of five for better optimization, and fortunately, none of them had violated the rule. Conclusion: The above results indicates that compound C2 is a relatively active and selective hit molecule that can be structurally modified to enhance the DPP-IV inhibitor's potency and overall pharmacological profile. From the present work, it has been concluded that substituted pyridine-3-carbohydrazide derivatives possess excellent DPP-IV inhibitory potential and can be better optimized further by generating more in vivo, in vitro models.