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 DiabetesMellitus

Background: One of the leading global metabolic diseases marked by insulin resistance andchronic hyperglycemia is type 2 diabetes mellitus (T2DM). Since the last decade, DPP-4 enzyme inhibitionhas proven 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 asDPP-IV inhibitors for the treatment of T2DM. Methods: The molecular docking was performed to study these derivatives' binding mode in the enzyme'sallosteric site. All the synthesized compounds were subjected for DPP-IV enzyme assay and in vivo antihyperglycemicactivity in STZ-induced diabetic rats. Results: The synthesized derivatives exhibited potent antidiabetic activity as compared to the standarddrug Sitagliptin. Out of sixteen compounds, A1, A4, B4, C2, C3, and D4 have shown promising antidiabeticactivity against the DPP-IV enzyme. The most promising compound, C2, showed a percentage inhibitionof 72.02±0.27 at 50 μM concentration. On the 21st-day, compound C2 showed a significant reductionin serum blood glucose level, i.e., 156.16±4.87 mg/dL, then diabetic control, which was280.00±13.29 mg/dL whereas, standard Sitagliptin showed 133.50±11.80 mg/dL. In the in vivo antihyperglycemicactivity, the compounds have exhibited good hypoglycemic potential in fasting blood glucosein the T2DM animal model. All the docked molecules have exhibited perfect binding affinity towardsthe active pocket of the enzyme. The synthesized derivatives were screened through Lipinski's ruleof five for better optimization, and fortunately, none of them violated the rule. Conclusion: The above results indicate that compound C2 is a relatively active and selective hit moleculethat can be structurally modified to enhance the DPP-IV inhibitor's potency and overall pharmacologicalprofile. From the present work, it has been concluded that substituted pyridine-3-carbohydrazide derivativespossess excellent DPP-IV inhibitory potential and can be better optimized further by generatingmore in vivo, in vitro models.