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.

糖尿病与阿尔茨海默病的双重负担凸显了对多功能治疗剂的迫切需求。本研究针对α-淀粉酶（α-amylase, AA）、α-葡萄糖苷酶（α-glucosidase, AG）、乙酰胆碱酯酶（acetylcholinesterase, AChE）与丁酰胆碱酯酶（butyrylcholinesterase, BChE），探索了胡椒醛（piperonal）衍生的席夫碱（Schiff base）衍生物作为潜在双功能酶抑制剂的可行性，为同时管控这两种疾病提供了颇具前景的策略。本研究合成了胡椒醛（又称天芥菜精（heliotropin））衍生的席夫碱衍生物，并对其结构进行了表征，同时针对已确立的糖尿病（diabetes mellitus, DM）与阿尔茨海默病（Alzheimer’s disease, AD）药物靶点开展活性评估，其中化合物7（半抑制浓度IC₅₀=5.73±0.01；3.52±0.02 μM）与化合物17（IC₅₀=10.91±0.02；7.38±0.02 μM）对α-葡萄糖苷酶与α-淀粉酶展现出强效抑制活性，其活性优于阳性对照阿卡波糖（IC₅₀=14.98±0.02；14.64±0.02 μM）。然而，在类似物7、9、10、14与15中，化合物7与9分别对乙酰胆碱酯酶与丁酰胆碱酯酶展现出显著抑制活性，其活性优于阳性对照多奈哌齐氯化物（IC₅₀=37.89±0.02；41.56±0.03 μM）。全面的动力学分析与分子对接研究验证了体外（in vitro）实验的结果，本研究同时评估了合成衍生物的抗氧化潜能，结果显示其具备显著的抗氧化活性。上述互补性研究筛选出多个候选化合物，有望进一步开发为同时针对糖尿病与阿尔茨海默病的治疗药物。