One-pot four-component synthesis of thiazolidin-2-imines using CuI/ZnII dual catalysis: A new class of acetylcholinesterase inhibitors

Abstract

An efficient one-pot four-component strategy involving aldehydes, amines, alkynes and isothiocyanates has been developed to access a novel series of thiazolidine-2-imines (5a-x). This process operates under the action of a cooperative catalysis composed of Cu(I) and Zn(II) delivering the desired five-membered heterocyclic compounds in good to excellent yields. Notably, this transformation avoids the use of pre-formed imines or propargylamines and proceeds via an intramolecular 5-exo-dig hydrothiolation reaction of the in situ formed propargyl thiourea. Furthermore, the biological application of these motifs was demonstrated in terms of their strong acetylcholinesterase (AChE) inhibitory activity where compound 5s was identified as the lead AChE inhibitor with an IC50 value of 0.0023 ± 0.0002 μM, 88-folds stronger inhibition than standard drug (neostigmine methyl sulphate; IC50 = 0.203 ± 0.004 μM). Molecular docking analysis reinforced the in vitro biological activity results revealing the formation of several useful interactions of the potent lead with amino acid residues in the active site of the enzyme.