Biological Evaluation of Anti-Cholinesterase Activity, in Silico Molecular Docking Studies, and DFT Calculations of Green Synthesized Thiadiazolo[3,2-a]pyrimidine Derivatives

Abstract

A series of [1,3,4] thiadiazolo[3,2-a]pyrimidine-6-carboxylate derivatives 4(a-n) have been designed and synthesized as inhibitors of acetylcholinesterase (AChE). Synthesizing of thiadiazolo[3,2-a] pyrimidines was carried out in a single step, one-pot reaction using aromatic aldehydes, ethyl acetoacetate and different derivatives of 1,3,4-thiadiazoles (with molar ratio of 1 : 2 : 1, respectively) in conjunction with the catalyst, anhydrous iron(III) chloride by a grinding method under solvent-free conditions at room temperature. The in-vitro studies exhibited good potency for inhibiting AChE comparable with donepezil as the reference drug. The best results were obtained by Ethyl 2-(4-nitroophenyl)-7-methyl-5-(pyridin-3-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylate 4n with IC₅₀ value of 0.082±0.001 μM which was comparable with AChE inhibitory effects of donepezil (IC₅₀ =0.079 μM).

Keywords: Alzheimer's disease; acetylcholinesterase; green synthesis; multi-component reaction (MCRs); solvent-free conditions; thiadiazolo[2,3-a]pyrimidines.