Ionophoric polyphenols are permeable to the blood –brain barrier, interact with human serum albumin and Calf Thymus DNA, and inhibit AChE enzymatic activity

AbstractAlzheimer ’s disease (AD) is the most common form of dementia that affects more than 40 million people around the world. The incidence is expected to rapidly increase due to the lack of any effective treatment. In previous work we synthesized a family of five ionophoric polyphenols (compounds1–5) that targeted important aspects related to AD, such as the toxic aggregation of amyloid- β peptides, the production of reactive oxygen species, or the excessive presence of Cu2+ ions. Here, in order to gain insights into their potential therapeutic value, we have tested the ability of compounds1–5 to cross the blood –brain barrier (BBB), to interact with human serum albumin (HSA) andCalf Thymus (ct) DNA, and to inhibit acetylcholinesterase (AChE). We performed BBB permeability and efflux mechanisms studies by means of the in vitro parallel artificial membrane permeability assay (PAMPA-BBB) and several in silico methods, while fluorescence, UV –visible, and circular dichroism spectroscopies were used to determine their ability to interact with HSA and ctDNA. Our results show that all five ionophoric polyphenols can effectively cross the BBB, and can form adducts with both HSA and ctDNA through one binding site and with association const ants ranging from 104 to 106 M−1, while still maintaining levels of unbound drug to protein within therapeutic range. Docking and molecular dynamics simulations show that the ionophoric polyphenols preferably bind the hydrophobic...
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research