Synthesis and Biological Evaluation of Piperidine-Linked Schiff Base Derivatives as Potential α-Amylase Inhibitors

Introduction: Piperidine scaffolds have attracted considerable attention for their diverse biological activities. The objective of this study is to design and synthesize piperidinebased Schiff base derivatives and evaluate their α-amylase inhibitory activity to identify potent antidiabetic candidates based on structure-activity relationships. Methods: Piperidine-based Schiff base derivatives were synthesized via condensation reactions and characterized using spectroscopic techniques, including FTIR, NMR, and mass spectrometry. Their antidiabetic potential was assessed through in vitro α-amylase inhibition assays. The inhibitory activity was quantified using a colorimetric DNSA method, measuring the reduction in maltose release. At 1 mg/mL, all compounds and the standard were assayed. Structure-activity relationship (SAR) analysis was conducted to correlate the electronic nature and position of substituents with enzyme inhibition efficiency. Results: The study revealed that para-substituted electron-withdrawing groups (EWGs), specifically fluoro (5a) and chloro (5c), exhibited the highest α-amylase inhibition rates of 75.17 ± 0.73% and 71.48 ± 0.70%, respectively. In contrast, derivatives with electron-donating groups (EDGs), such as methoxy (5i and 5j) and hydroxyl (5g and 5h), showed significantly lower inhibitory activity. These results indicate that para-positioned EWGs enhance enzyme inhibition, highlighting compounds 5a and 5c as promising antidiabetic candidates. Discussion: Substituent type and position on piperidine-based Schiff bases significantly affect α- amylase inhibition. Para-substituted EWGs, especially fluoro and chloro (5a, 5c), enhance activity through improved enzyme binding, while EDGs reduce efficacy. These findings support 5a and 5c as promising leads for antidiabetic drug development. Conclusion: In conclusion, piperidine-based Schiff base derivatives with para and metapositioned electron-withdrawing groups (EWGs), especially fluoro (5a) and chloro (5c), showed strong α-amylase inhibition, indicating their potential as antidiabetic agents. Electron-donating groups (EDGs) reduced activity, emphasizing the critical role of electronic effects on enzyme binding. These results support further development of EWG-substituted derivatives as promising α-amylase inhibitors.