Synthesis of (p‐tolyl)‐3(2H)pyridazinone Derivatives as Novel Acetylcholinesterase Inhibitors

Abstract

In this study, a series of N‐substituted‐(p‐tolyl)pyridazin‐3(2H)‐one derivatives were synthesized and evaluated for their AChE inhibitory activity. The chemical structures of novel compounds 5(a–m) were confirmed by 1H‐NMR, 13C‐NMR, IR and HRMS analysis. In order to eliminate the symptomatic effects of Alzheimer's disease, the proposed compounds were evaluated by acetylcholinesterase inhibition activity study in accordance with the cholinergic hypothesis. The results revealed that the N‐substituted‐(p‐tolyl)pyridazin‐3(2H)‐one derivatives inhibited the enzymes significantly. Ki values for acetylcholinesterase in the range of 0.56±0.15–4.12±1.42 μM. Compound 5 h demonstrated the greatest in AChE activity compared with tacrine (0.56±0.15 μM). Molecular docking studies were performed for all compounds that compared tacrine in AChE activity in‐vitro. As a result of molecular docking studies (ΔGBind, docking score, XP Gscore, Glide energy, Glide emodel), 5 f, 5 g and 5 h compounds showed good inhibitory properties in the AChE active site as in silico.

(p‐Chlorophenyl)‐3(2H)pyridazinone Derivatives: Synthesis, in Silico, and AChE/BChE Inhibitory Activity

“…In our previous study, electron‐releasing methyl‐substituted compounds were studied and their biological activities were examined [13] . In this study, with the addition of the chloro group into the structure, there was a slight decrease in the AChE inhibitory effect and the amino acid interactions in the active site of the enzyme were changed.…”

“…The peak of the H 4 proton of the 3(2H)-pyridazinone ring was observed as a doublet around 6.83-6.93 ppm, while the peak of the H 5 proton was observed as a doublet between 7.90-7.98 ppm. In the 13 C NMR spectrum, the specific thiocarbonyl group of triazole ring was observed in the range of 168.22-166.63 ppm. The peaks at the 3rd position of the pyridazinone ring and belonging to the carbonyl carbon were observed in the range of 158.68-158.82 ppm.…”

“…Melting points were measured on a hot stage microscope (Stuart SMP30) and are uncorrected. NMR spectra were recorded on a Bruker Avance Neo 500 MHz and Agilent Varian Mercury 400 MHz ( 1 H, 400 MHz, 500 MHz; 13 C, 100 MHz, 125 MHz), in CDCl 3 and DMSO-d 6 (internal standard tetramethylsilane). Chemical shifts (δ) are expressed as parts per million (ppm) downfield from tetramethylsilane (TMS) and the coupling constants (J) quoted in Hertz.…”

“…Supplementary data (synthetic procedures, biological assay methods and 1 H NMR & 13 C NMR and HRMS spectra of the synthesized compounds) associated with this article can be found, in the online version, at DOI: xxxxxxxxxx…”

Focusing on New Piperazinyl‐methyl‐3(2H)pyridazinone Based Derivatives: Design, Synthesis, Anticancer Activity and Computational Studies

“…Schrödinger 2021‐2 software program [22] was used for ligand preparation, protein preparation and determination of ligand‐target interactions in molecular docking. The method part of the molecular docking study was applied in previous studies [8k,l,23] . The reason why 3 aa compound is used as ligand in silico approaches is because it has given the best results against anti‐cancer experimentally.…”