Ahmad_2025_Future.Med.Chem_17_1959

BACKGROUND: The dual burden of diabetes and Alzheimer's highlights the urgent need for multifunctional therapeutic agents. This study explores piperonal-derived Schiff base derivatives as potential dual-action enzyme inhibitors against alpha-amylase (AA), alpha-glucosidase (AG), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), offers a promising strategy for managing both conditions. METHODS: Schiff base derivatives of piperonal (heliotropin) were synthesized, structurally characterized, and explored against established drug targets of diabetes mellitus (DM) and Alzheimer's disease (AD). RESULTS: Compounds 7 (IC(50) = 5.73 +/- 0.01; 3.52 +/- 0.02 microM) and 17 (IC(50) = 10.91 +/- 0.02; 7.38 +/- 0.02 microM) showed potent inhibitory effects against AG and AA enzymes, in comparison to acarbose (IC(50) = 14.98 +/- 0.02 microM; 14.64 +/- 0.02 microM). However, analogs 7, 9, 10, 14, and 15, compounds 7 (IC(50) = 2.92 +/- 0.02; 3.34 +/- 0.02 microM) and 9 (IC(50) = 8.16 +/- 0.03; 7.19 +/- 0.03 microM) showed remarkable inhibitory results against AChE and BChE, respectively, compared to standard donepezil chloride (IC(50) = 37.89 +/- 0.02 microM; 41.56 +/- 0.03 microM). Comprehensive kinetic analyses and molecular docking supported findings by in vitro studies. Synthesized derivatives were also checked for their antioxidant potential and demonstrated significant activity. CONCLUSION: These complementary studies highlight several hit candidates for further development as therapeutic agents against DM and AD.