In Silico Design and Green Synthesis of Polyhydroxy Conjugated Piperidine and Pyrrolidine Derivatives for In vitro Antiglycation Activity

Abstract The research work focuses on the design and development of a novel series of polyhydroxy-conjugated piperidine and pyrrolidine derivatives via microwave-assisted green synthesis, achieving high yields (82–87%) while providing a sustainable, energy-efficient alternative to conventional approaches. Physicochemical and spectroscopic techniques comprehensively characterized the synthesized derivatives. Their inhibitory activity against α-amylase, α-glucosidase, and advanced glycation end products formation was assessed through in vitro assays. Among the synthesized derivatives, 2,3,4,5,6-Pentahydroxyhexyl [3-phenyl-3-(p-tolylimino)propyl]prolinate exhibited dual inhibition of α-amylase (IC50 = 23.67 ± 0.91 µM) and α-glucosidase (IC50 = 38.08 ± 0.57 µM), surpassing that of rutin. In antiglycation assays, the most active synthesized derivatives significantly reduced the formation of AGEs by reducing fructosamine level, protein carbonylation, thiol oxidation, and congo red binding. The structure-activity relationship (SAR) analysis indicated that the electron-donating substituents significantly enhanced biological activity. Further, molecular docking simulations validated the binding interactions with human serum albumin (PDB ID: 4IW1) and supported the mechanistic insights into their mode of action. Notably, pyrrolidine derivatives demonstrated superior efficacy compared to their piperidines, attributed to their enhanced conformational flexibility and synergistic polyhydroxy interactions, facilitated hydrogen bonding, metal chelation, and nucleophilic reactivity toward carbonyl species. Overall, these findings highlight green-synthesized polyhydroxy-conjugated piperidine and pyrrolidine derivatives, particularly this compound, as promising scaffolds for antiglycation therapy and modulation of diabetes-associated complications.