One-pot three-component synthesis of novel pyrazolo-acridine derivatives and assessment of their acetylcholinesterase inhibitory properties: An in vitro and in silico study

Abstract

In this study, the synthesis and characterization of newly designed compounds containing pyrazole, acridine, and benzothiazole groups with their biological activity potentials were evaluated. For this purpose, the starting compound of our study, 1-(benzo[d]thiazol-2-yl)-3-(4-chlorophenyl)-1H-pyrazole-4-carbaldehyde (4), was synthesized according to the Vilsmeier-Haack method. Afterward, a series of new pyrazolo-acridine derivatives (7a-l) were obtained as a result of one-pot three-component reaction of compound 1 with 5,5-dimethyl cyclohexane-1,3‑dione and various aromatic amines. The structures of the synthesized compounds were characterized using FT-IR, 1H NMR, 13C NMR, Mass spectroscopy techniques, and elemental analysis. Then, the enzyme inhibition effects of these compounds on acetylcholinesterase (AChE) were investigated. According to the in vitro AChE enzyme activity studies, the most effective inhibitions of the compounds 7f (0.76±0.19 µM), 7d (0.82±0.33 µM), and 7e (1.70±1.66 µM) were determined from their low Ki values. On the other hand, in silico molecular docking interactions of the respective compounds with AChE (pdb id: 4EY9) were carried out by using AutoDock Vina software. The molecular docking analyses showed the effective molecular interactions of all compounds (7a-7l) with the AChE enzyme from their low binding energy values.