Synthesis, characterization, crystal structure, and cholinesterase inhibitory activity of 2-phenylthiazole derivatives

A series of 2-phenylthiazole derivatives were synthesized, characterized, and appraised as cholinesterase inhibitors. The structures of the 2-phenylthiazole derivatives were characterized by FT-IR, HRMS, 1 H NMR, 13 C NMR spectroscopy, and single-crystal X-ray diffraction studies. Compound 5a is a monoclinic crystal system with space group P2 1 . Compound 5c has an orthorhombic crystal system with the space group P2 1 2 1 2 1 . The cholinesterase inhibitory effects of synthetic 2-phenylthiazole derivatives were determined by Ellman's method. Most 2-phenylthiazole compounds possessed potent acetylcholinesterase inhibitory effects and weak butyrylcholinesterase inhibitory activities. Compound 5a has the best inhibitory effect on acetylcholinesterase, with an IC 50 of 0.031 mu M which was comparable to that of donepezil (IC 50 = 0.039 mu M). Molecular docking, molecular dynamics simulation, and binding free energy calculation/MM-GBSA revealed that compound 5a interacts with the peripheral anion site (PAS) of acetylcholinesterase stably. In conclusion, compound 5a is promising as an acetylcholinesterase inhibitor, which can be used as a leading compound for Alzheimer's disease in-depth research and development.(c) 2023 Elsevier B.V. All rights reserved.