Imidazol‐2‐Ylidene‐Silver(I) Complexes Bearing 4‐Acetylphenyl Side Arm: Design, Synthesis, Characterization, Crystal Structure, and Inhibitory Properties Against Some Metabolic Enzymes

Abstract

ABSTRACTHerein, the synthesis of silver(I)‐N‐heterocyclic carbene (Ag(I)NHC) complexes is presented. These complexes were synthesized from imidazolium salts and silver oxide via the deprotonation method. Ag(I)NHC complexes were characterized using various spectroscopic and analytical techniques, including FTIR, NMR, and elemental analysis. The single crystal structures of the complexes 1e and 1g were illuminated through x‐ray crystallography. The study demonstrates that the geometrical characteristics of both complexes closely match those of previously described complexes with a comparable ligand structure. Acetylcholinesterase (AChE) inhibitors prevent the excessive breakdown of acetylcholine by acting on acetylcholinesterase in its neurotransmission. In this way, they help to improve cognitive functions in patients with AD. On the other hand, human carbonic anhydrase inhibitors (CAIs) have been used clinically for many years as antiepileptic, antiglaucoma, antimetastatic, antitumor, and diuretic agents. In this study, the enzyme inhibition abilities of seven imidazol‐2‐ylidene‐silver(I) complexes bearing 4‐acetylphenyl side arm were examined against AChE and hCAs. These molecules exhibited a highly potent inhibition effect on AChE and hCAs (Ki values are in the range of 16.27 ± 1.81 to 130.79 ± 11.98 nM for AChE, 13.22 ± 1.88 to 182.14 ± 33.93 nM for hCA I, and 12.72 ± 1.99 to 62.36 ± 9.21 nM for hCA II). Novel imidazol‐2‐ylidene‐silver(I) complexes bearing 4‐acetylphenyl side arms 1a–g displayed efficient inhibitory profiles for the examined metabolic enzymes. Docking was additionally performed to investigate the interactions of the current complexes 1a–g with hCA I, hCA II, and AChE proteins. It has been determined that compound 1d has activity against all the tested proteins, with the most effective interaction observed with hCA I. The pharmacokinetic properties of the three top potent complexes for each target against the related proteins were also examined using the SwissADME and pkCSM web tools. In the meantime, the stabilities of the complexes with the highest binding potential according to the docking study were assessed through molecular dynamics simulation. The AChE–1a complex was found to be the one with relatively high stability. Also, further energy computations were made by using the MD simulation results. The compounds have been estimated to bind strongly with their targets.