Benzimidazolium salts bearing the trifluoromethyl group as organofluorine compounds: Synthesis, characterization, crystal structure, in silico study, and inhibitory profiles against acetylcholinesterase and α‐glycosidase

Abstract

Here, we report the synthesis, characterization, and biological activities of a series of benzimidazolium salts bearing the trifluoromethylbenzyl group. All benzimidazolium salts were characterized by using nuclear magnetic resonance (NMR) ( 1 H NMR and 13 C NMR), Fourier transform-infrared spectroscopy, and elemental analysis techniques. The crystal structures of some of these compounds were obtained by the single-crystal X-ray diffraction method. Furthermore, the acetylcholinesterase (AChE) and α-glycosidase (α-Gly) enzyme inhibition activities of these compounds were investigated. The obtained results revealed that 2e, with K i value of 1.36 ± 0.34 µM against AChE and 3d with K i value of 91.37 ± 10.38 µM against α-Gly, were the most potent compounds against both assigned enzymes. It should be noted that most of the synthesized compounds were more potent than standard inhibitor tacrine (TAC) against AChE. In silico studies, we focused on compound 2e, 3d, 3e, and 3f as potent inhibitors of AChE and α-Gly, the compound 2e showed good binding energy (−10.23 kcal/mol), among the three selected compounds and positive control (−10.18, −10.08, and −7.37 kcal/mol for 3d, 3f, and TAC, respectively). Likewise, as a result of the same compounds against the α-Gly enzyme, the compound 3d had the highest binding affinity (−8.39 kcal/mol) between the four selected compounds and the positive control (−8.27, −8.10, −8.06, and −7.53 kcal/mol for 3f, 3e, 2e, and acarbose, respectively). From the absorption, distribution, metabolism, excretion, and toxicity analyses, it can be concluded that the compounds under consideration exhibited more drug-likeness properties in the prediction studies compared to positive controls.

Benzimidazolium Salts Containing Trifluoromethoxybenzyl: Synthesis, Characterization, Crystal Structure, Molecular Docking Studies and Enzymes Inhibitory Properties

“…They showed benzimidazolium salts effectively inhibited AChE with K i s ranging from 0.94 to 10.24 μM. Tercan et al [46] . reported the synthesis and inhibition effect of benzimidazolium salts bearing the trifluoromethylbenzyl group.…”

“…They showed benzimidazolium salts effectively inhibited AChE with K i s ranging from 0.94 to 10.24 μM. Tercan et al [46] reported the synthesis and inhibition effect of benzimidazolium salts bearing the trifluoromethylbenzyl group. They found K i s in the range of 0.42 � 0.01 -1.27 � 0.16 μM for α-glycosidase and 1.36 � 0.34 -13.61 � 2.84 μM for AChE.…”

“…While examining the crystal structure of the 1f , two different crystals were encountered in the crystal selection. When both crystals were examined, it was determined that they were conformational polymorphs [46,47] . Inhibition effects of these benzimidazolium salts against AChE and hCAs enzymes were investigated.…”

“…When both crystals were examined, it was determined that they were conformational polymorphs. [46,47] Inhibition effects of these benzimidazolium salts against AChE and hCAs enzymes were investigated. Furthermore, molecular docking is a computer simulation method that is exerted to model the interaction between a small molecule as a ligand and a larger molecule as a target based on the spatial form and energy of the respective molecules that match each other.…”

Benzimidazolium Salts Bearing Nitrile Moieties: Synthesis, Enzyme Inhibition Profiling, and Molecular Docking Analysis for Carbonic Anhydrase and Acetylcholinesterase

“…The crude product was crystallized from ethyl alcohol/diethyl ether (1 : 3) at room temperature to afford the 3-benzyl-1-(3-cyanopropyl)benzimidazolium salt. [52] Yield: 85 % (0.708 g). m.p.…”