New Pyrimidine and Pyridine Derivatives as Multitarget Cholinesterase Inhibitors: Design, Synthesis, and In Vitro and In Cellulo Evaluation

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 mu M) and compound 22 on equine BChE (eqBChE) (K-i = 0.099 mu M). 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 Cu2+ and Fe3+ and that compounds 18, 20, and 30 have antioxidant properties. Interestingly, some compounds were also able to reduce A beta(42) and tau aggregation, with compound 28 being the most potent (22.3 and 17.0% inhibition at 100 mu M on A beta(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.

Automated summary

A new series of dual binding site inhibitors were designed to effectively inhibit cholinesterases while possessing antioxidant and anti-aggregation properties against dementia-related proteins. These compounds exhibit low cytotoxicity and are predicted to be able to penetrate the blood-brain barrier.