Synthesis, biological activity, X-ray crystallographic, DFT calculations and molecular dynamics simulation studies of 2-phenylthiazole-1,3,5-triazine derivatives as potential cholinesterase inhibitors

Abstract

Seven 2-phenylthiazole-1,3,5-triazine derivatives were synthesized and estimated for cholinesterase inhibitory activity. All target compounds were characterized by 1H NMR, 13C NMR, FT-IR, and HRMS, and their purity was tested by HPLC to be above 99 %. The in vitro enzyme inhibitory activity assays determined that the majority of compounds exhibited moderate to good inhibitory effects on acetylcholinesterase or butyrylcholinesterase and compound 6g displayed the best acetylcholinesterase (IC50 = 0.26 μM) and butyrylcholinesterase inhibitory activity (IC50 = 0.78 μM). The structures of compounds 6a and 6g was further investigated by single-crystal X-ray diffraction, and the Hirshfeld surfaces, crystal voids, and molecular energy framework analysis were further discussed to study the molecular conformations, crystal packing modes, intermolecular interactions, and their energies. What's more, the density functional theory calculations including frontier molecular orbitals, global reactivity descriptors, and molecular electrostatic potential were carried out to reveal the chemical reactivity and stability of 6a and 6g molecules. Molecular docking study indicated that compound 6g could not only interact with acetylcholinesterase but also with butyrylcholinesterase. Molecular dynamics simulations study showed that compound 6g could bind to acetylcholinesterase stably. In addition, ADMET properties prediction implied the drug-like properties and safety of seven compounds. Considering these results, several of the target compounds could work as novel cholinesterase inhibitors, and compound 6g may possess the potential to become a lead compound to develop novel anti-Alzheimer drugs.