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

MedChemComm
2019.0

Abstract

A novel series of 2-pyrazoline derivatives were designed, synthesized, and evaluated for cholinesterase (ChE) inhibitory, Aβ anti-aggregating and neuroprotective activities. Among these, <b>3d</b>, <b>3e</b>, <b>3g</b>, and <b>3h</b> were established as the most potent and selective BChE inhibitors (IC<sub>50</sub> = 0.5-3.9 μM), while <b>3f</b> presented dual inhibitory activity against BChE and AChE (IC<sub>50</sub> = 6.0 and 6.5 μM, respectively). Kinetic analyses revealed that <b>3g</b> is a partial noncompetitive inhibitor of BChE (Ki = 2.22 μM), while <b>3f</b> exerts competitive inhibition on AChE (Ki = 0.63 μM). The active compounds were subsequently screened for further assessments. <b>3f</b>, <b>3g</b> and <b>3h</b> reduced Aβ<sub>1-42</sub> aggregation levels significantly (72.6, 83.4 and 63.4%, respectively). In addition, <b>3f</b> demonstrated outstanding neuroprotective effects against Aβ<sub>1-42</sub>-induced and H<sub>2</sub>O<sub>2</sub>-induced cell toxicity (95.6 and 93.6%, respectively). Molecular docking studies were performed with <b>3g</b> and <b>3f</b> to investigate binding interactions inside the active sites of BChE and AChE. Compounds <b>3g</b> and <b>3f</b> might have the multifunctional potential for use against Alzheimer's disease.

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