Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, with current treatments focused on inhibiting acetylcholinesterase (AChE) to sustain acetylcholine levels in brain. Objective: In this work, three new calixarene derivatives 3, 5, and 7 were synthesized and evaluated against AChE in vitro and in silico. Methods: Firstly, target compounds 3, 5, and 7 were synthesized from calix4arene (1), and after characterization, they were evaluated in vitro against AChE. The most potent compound, as determined by in vitro evaluation, underwent additional in silico studies, including a docking study, pharmacokinetics analysis, and density functional theory (DFT) analysis. Results: The most potent compound was the pyridin-2-yl-chalcone derivative 7, which interacted well with the active site of AChE. This compound also has an acceptable energy gap between HOMO and LUMO orbitals as a drug candidate. The pharmacokinetics and toxicity profiles of new calixarene derivatives 3, 5, and 7 were satisfactory. Conclusion: Our in vitro and in silico results suggest that the calixarene derivatives are promising candidates for targeting AChE.
Ojani et al. (2025) studied this question.