Design, Synthesis, and Evaluation of New Pyrazolines As Small Molecule Inhibitors of Acetylcholinesterase.

In pursuit of identifying small molecule inhibitors of acetylcholinesterase (AChE), the synthesis of new 2-pyrazolines was performed efficiently. A modified spectrophotometric method was used to examine their inhibitory effects on AChE as well as butyrylcholinesterase. Four compounds (, , , and ) were identified as selective AChE inhibitors. Molecular docking studies were conducted to explore their potential interactions with the active site of AChE (PDB code: 4EY7). 1-(3-Nitrophenyl)-3-(thiophen-3-yl)-5-[4-(4-morpholinyl)phenyl]-2-pyrazoline () exerted significant AChE inhibitory action with an IC value of 0.040 μM close to donepezil (IC = 0.021 μM). In addition to π-π interactions with Tyr341, Tyr124, and Trp86 residues, compound was also capable of forming two hydrogen bonds and a salt bridge at the active site of AChE thanks to its nitro group at the position of the phenyl moiety linked to the position of the pyrazoline scaffold. The higher inhibitory effect of compound on AChE when compared to other compounds in this series might be explained by these additional interactions. Based on the parallel artificial membrane permeability assay, compound was found to have high blood-brain barrier permeability. and studies suggest that compound is a potent inhibitor of AChE, which is an important target for neurodegenerative disorders, particularly Alzheimer's disease.