Synthesis and evaluation of the acetylcholinesterase inhibitory effect of novel heteroaromatic derivatives bearing a 2-(5-(pyridin-2-yl)-1H-tetrazol-1-yl)acetamide scaffold

Tóm tắt

Acetylcholinesterase (AChE) has been one of the important and potential targets in the discovery, and development of new drugs for treating and slowing the progression of Alzheimer's disease (AD). Starting from 2-pyridine carbonitrile, four novel derivatives (IVa, IVb, IVc, IVd) bearing the 2-(5-(pyridin-2-yl)-1H-tetrazol-1-yl)acetamide scaffold were synthesized through [3+2] cycloaddition, N-alkylation, saponification, acidification, and finally amidation. The purity of compounds was confirmed by measuring melting-point and using thin layer chromatography (TLC). The structures of synthesized compounds were determined by various spectroscopy methods, including infrared spectroscopy (IR), high-resolution mass spectrometry (HRMS), proton nuclear magnetic resonance spectrocopy (¹H-NMR), and carbon nuclear magnetic resonance spectrocopy (¹³C-NMR). Next, the synthesized compounds were evaluated for their inhibitory effect on the AChE enzyme, and their molecular docking, and drug-like properties were studied. The results showed that all four synthesized compounds exhibited AChE inhibitory activity ranging from 20.0% to 50.8% at the concentration of 256 µM. Additionally, none of four compounds violated Linpiski’s rule of five or Veber’s rule. Moreover, the biological activities and molecular docking results indicated that the naphthalene (IVd) or the pyridine (IVc) substituents linked to the 2-(5-(pyridin-2-yl)-1H-tetrazol-1-yl)acetamide scaffold notiecably increase the AChE inhibitory effect. In contrast, the electron-donating group (-OCH₃) substituted phenyl ring reduced the ability to inhibit AChE. This research suggests potential structural frameworks for synthesizing AChE inhibitor derivatives for treating AD.