Pincer Ligands as Multifunctional Agents for Alzheimer's Copper Dysregulation and Oxidative Stress: A Computational Evaluation

Abstract

AbstractAlzheimer's disease (AD) is the most common form of dementia worldwide, affecting millions of people around the globe. AD is characterized by different pathologies being beta‐amyloid (Aβ) plaque formation, metal ion dysregulation, and oxidative stress (OS) central topics under investigation. Copper‐Aβ complexes have been shown to induce catalytic hydrogen peroxide formation and increase OS in the brain leading to neuronal death. Pincer‐type compounds are tridentate ligands that coordinate metals in a planar fashion whose properties can be tuned via group substitutions, giving rise to many possibilities in catalysis and drug discovery. In this work we evaluated the potential pharmaceutical activity of 26 pincer compounds in AD's copper ion‐related oxidative stress framework. In this sense, four key aspects were considered: 1) Lipinski's rule of five, 2) blood‐brain barrier permeation, 3) standard reduction potential (SRP) of the formed copper complexes, and 4) the ligand's affinity towards copper cations. The evaluation of these criteria was performed by means of bioinformatic tools and electronic structure calculations at the DFT level of theory. Our results suggest that two compounds from this set are potential antioxidant agents, whereas five of them are promissory distributor‐like compounds in the context of AD.