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

Tóm tắt

Acetylcholinesterase (AChE) is a key therapeutic target for developing new Alzheimer's disease (AD) treatments due to its regulatory function in acetylcholine hydrolysis. Based on the structure of AChE active site and the known AChE inhibitors phthalimide derivatives, three novel compounds (II, III, and V) bearing the 2-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)alkyl scaffold were designed. These compounds were synthesized using a [3+2] cycloaddition, N-alkylation, and reductive amination reactions. Their purity and structure were confirmed using various analytical techniques, including thin layer chromatography (TLC), high-resolution mass spectrometry (HRMS), proton nuclear magnetic resonance spectroscopy (¹H-NMR), and carbon nuclear magnetic resonance spectroscopy (¹³C-NMR). These compounds were evaluated for their ability to inhibit AChE. All three compounds showed weak inhibitory activity with IC₅₀ values between 182.31 and 213.70 μM. None of them violated Lipinski's or Veber's rules-the criteria underscores the drug-likeness of the molecules, this compliance has positive implications for the design and development of similar compounds in the future. The biological activities results suggested that the benzyl (V) substituent slightly enhances AChE inhibition compared to phthalimide (II, III), demonstrating the inhibitory efficacy of halogen-substituted benzyl groups and the 2-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)alkyl scaffold. This research contributed to the development of a novel scaffold for AChE inhibitors, which are potential drugs for treating AD.

Keywords: Alzheimer, Acetylcholinesterase inhibitors, Tetrazole, Phthalimide