Design, synthesis, biological activity, molecular docking, and molecular dynamics of novel benzimidazole derivatives as potential AChE/MAO‐B dual inhibitors

Abstract

To develop new acetylcholinesterase (AChE)–monoamine oxidase‐B (MAO‐B) dual inhibitors against Alzheimer's disease, the benzimidazole ring, which has a propargyl side chain with previously proven selective MAO‐B inhibitory activity, was used as the main structure. Moreover, like donepezil, it was thought that the enzyme AChE would provide π–π interactions with the peripheral anionic side in this structure. Piperazine derivatives were chosen for the cationic active site. The synthesis of the compounds was carried out in five steps. The structures of the compounds were determined using 1H‐NMR (nuclear magnetic resonance), 13C‐NMR, and high‐resolution mass spectrometry spectroscopic methods. First, the in vitro AChE, butyrylcholinesterase (BChE), MAO‐A, and MAO‐B inhibitory potentials of the obtained compounds were investigated. As a result of activity tests, compounds 5b, 5e, 5g, and 5h showed inhibitory activity against AChE; compounds 5e and 5g showed inhibitory activity against MAO‐B. None of the compounds showed inhibitory activity against BChE or MAO‐A. Compounds 5e and 5g showed dual inhibition. Among these compounds, compound 5g had inhibition potential similar to that of donepezil and selegiline. For compound 5g, further kinetic studies and Aβ‐plaque inhibitory potentials were investigated using in vitro methods. Molecular docking studies were performed using both AChE and hMAO‐B crystals to elucidate the compound's interactions with the enzyme active site. The binding modes of the compound on AChE were fully elucidated by molecular dynamics studies.

Design, Synthesis, and In Vitro and In Silico Approaches of Novel Indanone Derivatives as Multifunctional Anti-Alzheimer Agents

“…The category of reversible inhibition is further subdivided into mixed, competitive, noncompetitive, and uncompetitive types. In Lineweaver–Burk graphs, the kind of inhibition is classified as uncompetitive if four lines are parallel, competitive if they intersect on the y -axis, noncompetitive if they do so on the x -axis, and mixed if they cross in any of the graphic’s regions but not on any of its axes. − …”

“…According to the modified Ellman approach outlined in our team’s earlier work, the AChE and BChE inhibitory activities of the obtained compounds were evaluated. − The enzymes utilized in the experiment were human AChE (CAS no. 9000-81-1) and human BChE (CAS no.…”

“…Separate measurements were conducted both with and without an inhibitor. Using the Microsoft Office Excel 2013 program, the resulting absorbance values were compared to various substrate concentrations, and Lineweaver–Burk plots were created. − …”

“…The Beta Amyloid 1–42 (Aβ42) Ligand Screening Assay kit (BioVision, Milpitas, CA) technique based on the fluorometric approach served as the basis for the experimental process. ,, …”

Synthesis and Cholinesterase Inhibitory Potentials of (5-formylfuran-2-yl) methyl 3,4-dimethoxy/nitro benzoates

“…Tacrine is a competitive/non-competitive reversible ChEs inhibitor approved by the FDA for use in Alzheimer's. (Osmaniye et al, 2022) Tacrine, which has IC50 values of low micromolar concentrations against ChEs, is used as a reference inhibitor in many studies on in vitro ChE inhibition. (Özbey et al, 2016;Yılmaz et al, 2016) However, due to the hepatotoxic effects of tacrine, its clinical use is very limited.…”