Synthesis, characterization and In-silico study of some 4-nitro-N-(piperidin-4-yl)benzamide derivatives as GPR119 agonists for the treatment of diabetes

4-Nitro-N-(piperidin-4-yl)benzamide (S5I2) is a key pharmacophore for GPR119 agonists, promoting insulin secretion and incretin release without causing hypoglycemia. Its structural design enhances receptor binding, bioavailability, and glucose regulation, making it a promising candidate for diabetes treatment. A series of derivatives (S5F1-S5F7) was synthesized through a two-step process. Initially, 4-nitrobenzoic acid (1) reacted with tert-butyl 4-aminopiperidine-1-carboxylate (2) to form intermediate-1, S5I1, which was then deprotected using TFA to yield intermediate-2, S5I2. The final compounds were synthesized via amidation coupling with substituted benzoic and nicotinic acids/chlorides using 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), Hydroxybenzotriazole (HOBT)/ Hexafluorophosphate aza benzotriazole tetramethyl uronium (HATU), Triethylamine (TEA), and Dimethylformamide (DMF). Molecular docking (AutoDock 4.0) evaluated ligand interactions with the GPR119 receptor, designed through homology modeling (MODELLER). SwissADME software was used to assess pharmacokinetic properties. Docking results identified S5F4 and S5F2 showed the best binding affinity (-12.8) and (-10.7) respectively in comparison to reference molecule AR231453 with (-11) and emerged as potent ligands. The integration of fluorine atoms in S5F4, owing to their high electronegativity and small size, can strengthen receptor binding affinity and optimize pharmacokinetic properties. Structural confirmation and validation of synthesized compounds were achieved through FT-IR,¹H/¹³C NMR, and LC-MS.