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

ABSTRACT 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 µM which was comparable to that of donepezil (IC 50  = 0.039 µM). 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.