Novel Approach to Synthesis of Diaryl Tacrine Derivatives and Evaluation of Their Inhibitory Effects on Cholinesterase Enzymes

Abstract

The development of effective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors remains a crucial objective in the treatment of neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, a novel synthetic approach was established to prepare a series of diaryl-substituted tacrine derivatives. Initially, brominated aminobenzonitrile was subjected to Suzuki-Miyaura cross-coupling reactions with various aryl boronic acids to yielding diaryl-substituted aminobenzonitriles at yields of 60%–72%. These intermediates were then cyclized with cyclohexanone and cycloheptanone under Friedländer conditions using BF₃·OEt₂ as a catalyst, affording six- and seven-membered diaryl tacrine analogues in yields of 52%–68%. All synthesized compounds were characterized by NMR, IR, and elemental analysis. The inhibitory activities of these compounds (7–16) against AChE and BChE were evaluated, and several analogs demonstrated potent dual-enzyme inhibition at nanomolar concentrations. Notably, compounds 8 and 13 exhibited half maximal inhibitory concentration (IC₅₀) values of 6.848 and 8.545 nmol/L for BChE, respectively, indicating strong potential as selective cholinesterase inhibitors. The structure-activity relationship (SAR) analysis revealed the influence of aryl substituents on the potency and selectivity of enzyme inhibition. Compared to previously reported tacrine derivatives, the newly synthesized analogs exhibited superior inhibitory profiles, indicating their potential as lead compounds for further development in AD therapeutics.

Keywords

Acetylcholinesterase (AChE) / Aminobenzonitrile / Aryl / Butylcholinesterase (BChE) / Structure-activity relationship (SAR) / Tacrine

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Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH