Synthesis, molecular docking, and biological evaluation of novel 2-pyrazoline derivatives as multifunctional agents for the treatment of Alzheimer's disease.

A novel series of 2-pyrazoline derivatives were designed, synthesized, and evaluated for cholinesterase (ChE) inhibitory, Aβ anti-aggregating and neuroprotective activities. Among these, , , , and were established as the most potent and selective BChE inhibitors (IC = 0.5-3.9 μM), while presented dual inhibitory activity against BChE and AChE (IC = 6.0 and 6.5 μM, respectively). Kinetic analyses revealed that is a partial noncompetitive inhibitor of BChE (Ki = 2.22 μM), while exerts competitive inhibition on AChE (Ki = 0.63 μM). The active compounds were subsequently screened for further assessments. , and reduced Aβ aggregation levels significantly (72.6, 83.4 and 63.4%, respectively). In addition, demonstrated outstanding neuroprotective effects against Aβ-induced and HO-induced cell toxicity (95.6 and 93.6%, respectively). Molecular docking studies were performed with and to investigate binding interactions inside the active sites of BChE and AChE. Compounds and might have the multifunctional potential for use against Alzheimer's disease.