Thioether-substituted Benzimidazolium Salts: Synthesis, Characterization, Crystal Structure, and Their Inhibitory Properties Against Acetylcholinesterase and Xanthine Oxidase

•Benzimidazolium salts bearing 4-(methylthio)benzyl group were synthesized.•All compounds were characterized by NMR and FTIR spectroscopic techniques.•One compound was examined by the single-crystal X-ray diffraction method.•Inhibitory effects of all compounds were been tested against XO and AChE enzymes.•Molecular docking work was conducted on the chosen compounds against AChE and XO. The sulfurous compounds are known as organosulfur, which has been associated with numerous biological activities in both natural products and synthetic organic compounds. In this work, we present the synthesis of a series of 4-(methylthio)benzyl substituted benzimidazolium salts. All compounds were characterized using NMR (1H and 13C) and FTIR spectroscopic methods as well as an elemental analysis technique. The molecular and crystal structures of the compound 1a were determined by X-ray crystallography revealing that the compound crystallized in the trigonal space group R-3. Enzyme inhibition studies demonstrated that a new series of sulfurous compounds precursors were highly potent inhibitors for xanthine oxidase (XO) and acetylcholinesterase (AChE) enzyme. The IC50 values were found in the range of 0.548 ± 0.033 to 0.725 ± 0.043 µM for XO promising strategy for the treatment from gout disease, while IC50 values were found in the range 0.813 ± 0.076 to 1.149 ± 0.072 µM toward AChE as the key enzyme promising strategy for the treatment of neurological disorders such as Alzheimer's disease (AD). Furthermore, pharmacodynamics studies prove the binding interaction patterns, structural orientations and drug potential of sulfide derivatives in the binding sites of xanthine oxidase (XO) and acetylcholinesterase (AChE) enzymes. Potential inhibitors (compounds 1d-f) were compared with standard compounds allopurinol (for XO) and donepezil (for AChE). Compared to the positive compound of target XO, the 4-vinylbenzyl group of potential compound 1f and the 4-methylbenzyl group of compound le more effectively formed electrostatic and hydrophobic interactions with the target's interaction site. While donepezil as standard compound interacts only at the peripheral anionic site of AChE, the related compounds interact with both regions (PAS and CAS sites) of the same target. These compounds were placed at the active sites of the respective targets by molecular docking method using AutoDock software. Binding energy, binding modes and interaction types were used to evaluate the series of 4-(m