Bortolami_2021_ACS.Chem.Neurosci__

A new series of pyrimidine and pyridine diamines was designed as dual binding site inhibitors of cholinesterases (ChEs), characterized by two small aromatic moieties separated by a diaminoalkyl flexible linker. Many compounds are mixed or uncompetitive acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) nanomolar inhibitors, with compound 9 being the most active on Electrophorus electricus AChE (EeAChE) (K(i) = 0.312 microM) and compound 22 on equine BChE (eqBChE) (K(i) = 0.099 microM). Molecular docking and molecular dynamic studies confirmed the interaction mode of our compounds with the enzymatic active site. UV-vis spectroscopic studies showed that these compounds can form complexes with Cu(2+) and Fe(3+) and that compounds 18, 20, and 30 have antioxidant properties. Interestingly, some compounds were also able to reduce Abeta(42) and tau aggregation, with compound 28 being the most potent (22.3 and 17.0% inhibition at 100 microM on Abeta(42) and tau, respectively). Moreover, the most active compounds showed low cytotoxicity on a human brain cell line and they were predicted as BBB-permeable.