Piperonal-derived Schiff base molecules as potential multi-target therapeutic agents against Alzheimer’s and diabetes

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 <i>α</i>-amylase (AA), <i>α</i>-glucosidase (AG), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), offers a promising strategy for managing both conditions. 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). Compounds <b>7</b> (IC₅₀ = 5.73 ± 0.01; 3.52 ± 0.02 <i>µ</i>M) and <b>17</b> (IC₅₀ = 10.91 ± 0.02; 7.38 ± 0.02 <i>µ</i>M) showed potent inhibitory effects against AG and AA enzymes, in comparison to acarbose (IC₅₀ = 14.98 ± 0.02 <i>µ</i>M; 14.64 ± 0.02 <i>µ</i>M). However, analogs <b>7</b>, <b>9</b>, <b>10</b>, <b>14</b>, and <b>15</b>, compounds <b>7</b> (IC₅₀ = 2.92 ± 0.02; 3.34 ± 0.02 <i>µ</i>M) and <b>9</b> (IC₅₀ = 8.16 ± 0.03; 7.19 ± 0.03 <i>µ</i>M) showed remarkable inhibitory results against AChE and BChE, respectively, compared to standard donepezil chloride (IC₅₀ = 37.89 ± 0.02 <i>µ</i>M; 41.56 ± 0.03 <i>µ</i>M). Comprehensive kinetic analyses and molecular docking supported findings by <i>in</i> <i>vitro</i> studies. Synthesized derivatives were also checked for their antioxidant potential and demonstrated significant activity. These complementary studies highlight several hit candidates for further development as therapeutic agents against DM and AD.