5(6)-Benzoyl-Substituted Benzimidazoles and Their Benzimidazolium Salts: Design, Synthesis, Characterization, Crystal Structure, and Some Metabolic Enzymes Inhibition Properties.

Herein, the synthesis of 1-alkyl-5(6)-benzoyl-substituted benzimidazoles and their 1,3-bisalkylbenzimidazolium halide salts are presented and evaluated for some metabolic enzyme inhibition. All compounds were characterized using various spectroscopic techniques. Single-crystal XRD analysis was performed to determine the molecular structure of two compounds. The newly synthesized compounds exhibited significant inhibitory effects against acetylcholinesterase (AChE) and human carbonic anhydrase isoforms I and II (hCA I and hCA II) enzymes. These compounds demonstrated promising inhibition profiles, with K values ranging from 12.4 ± 5.4 to 109.4 ± 49.9 nM for hCA I, 23.1 ± 11.2 to 115.0 ± 17.9 nM for hCA II, and 0.7 ± 0.3 to 4.4 ± 1.0 nM for AChE. In comparison, the reference compound acetazolamide showed K values of 30.5 ± 6.7 nM and 37.4 ± 7.8 nM against hCA I and hCA II isoenzymes, respectively. Additionally, tacrine, a known AChE inhibitor, exhibited a K value of 5.1 ± 2.7 nM. The dual inhibition of CA and AChE represents a valuable pharmacological approach with a wide range of therapeutic applications. The explanation and evaluation of the enzyme inhibition data obtained in line with the interactions of the synthesized compounds with hCA I, hCA II, and AChE enzymes were carried out by molecular docking studies. In particular, we focused on the three compounds (4e, 4f, and 4j for hCA I; 3g, 4f, and 4k for hCA II; and 4e, 4f, 4j, and 4l for AChE) with the highest potential activity with each enzyme. The physicochemical, ADME, drug-likeness, medicinal chemistry, and toxicity properties of the potential ligands were then predicted so that their drug candidate suitability for further studies is revealed.