Structures and Acetylcholinesterase Inhibition Abilities of some Derivatives Bearing (Pyridin-2-yl)tetrazole Scaffold

Abstract

Tetrazole derivatives are a prominent class of heterocycles that hold significant value in medicinal chemistry and drug design. Their importance stems from their bioisosteric resemblance to carboxylic acid and amide moieties and their favorable metabolic stability and other beneficial physicochemical properties. In light of this, novel derivatives bearing the (pyridine-2-yl)tetrazol scaffold were synthesized with the presence of acid, ester and amide moieties and evaluated for their inhibitory effects on the enzyme acetylcholinesterase (AChE). Through a three-step synthesis reaction initiated with 2-pyridine carbonitrile, compound IV was successfully obtained with II and III as the intermediates. All substances II - III - IV demonstrated inhibitory activity against the enzyme acetylcholinesterase. Notably, substance IV exhibited the highest percentage of inhibition, achieving 23,7 % at a concentration of 75 µM. Based on molecular docking simulations, compounds containing stronger nucleophilic substituents exhibit more robust AChE enzyme inhibitory activity due to a greater abundance of hydrogen bonds. This drug-likeness simulation and ADME prediction highlight the potential of tetrazole derivatives as a promising treatment for Alzheimer's disease.