A Series of New Hydrazone Derivatives: Synthesis, Molecular Docking and Anticholinesterase Activity Studies

Abstract

Background: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh), which is a significant neurotransmitter for regulation of cognition in animals. Inhibition of cholinesterases is an effective method to curb Alzheimer’s disease, a progressive and fatal neurological disorder. Objective: In this study, 30 new hydrazone derivatives were synthesized. Then we evaluated their anticholinesterase activity of compounds. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach. Methods: The compounds were synthesized by the reaction of various substituted/nonsubstituted benzaldehydes with 6-(substitute/nonsubstituephenyl)-3(2H)-pyridazinone-2-yl propiyohydrazide. Anticholinesterase activity of the compounds was determined using Ellman’s method. Molecular docking studies were done by using the ADT package version 1.5.6rc3 and showed by Maestro. RMSD values were obtained using Lamarckian Genetic Algorithm and scoring function of AutoDock 4.2 release 4.2.5.1 software. Results: The activities of the compounds were compared with galantamine as cholinesterase enzyme inhibitor, where some of the compounds showed higher BChE inhibitory activity than galantamine. Compound F111 was shown to be the best BChE inhibitor effective in 50 μM dose, providing 89.43% inhibition of BChE (IC50=4.27±0.36 μM). Conclusion: This study supports that novel hydrazone derivates may be used for the development of new BChE inhibitory agents.

Antioxidant Molecules Isolated from Edible Prostrate Knotweed: Rational Derivatization to Produce More Potent Molecules

“…Compound 5A was docked into the active sites of AChE, BChE, COX-1, COX-2, and 5-LOX. The three-dimensional structures of all the enzymes were obtained from the Protein Data Bank with accession codes 1EVE, 4BDS, 1EQG, 1CX2, and 6N2W, respectively [ 58 , 59 ].…”

Development of a Novel Class of Pyridazinone Derivatives as Selective MAO-B Inhibitors

“…The nucleophilic substitution reaction of 3,6-dichloropyridazine with phenylpiperazine or morpholine derivatives in ethanol was carried out to produce 3-chloro-6-substituted pyridazine. The hydrolysis of 3-chloro-6-(4-(3,4-dichlorophenyl)piperazine-1-yl)pyridazine by heating in glacial acetic acid afforded 6-(4-(3-Methoxy/3-trifluoromethylphenyl)piperazi ne-1-yl/morpholino)-3(2H)-pyridazinone [19]. Subsequently, the reaction of 6-(4-(3-methoxy /3-tifluoromethylphenyl)piperazine-1-yl/morpholino)-3(2H)-pyridazinone with ethyl bromoacetate in the presence of K 2 CO 3 in acetone replaced the hydrogen atom of tertiary nitrogen atom in the pyridazinone ring and formed ethyl 6-(4-(3-methoxy/3-trifluorome thylphenyl)piperazine-1-yl/morpholino)-3(2H)-pyridazinone-2-ylacetate.…”

Synthesis, Molecular Docking and Molecular Dynamics Simulation Studies of Some Pyridazinone Derivatives as Lipase Inhibitors

“…Overnight in acetone (40 mL), 0.01 mol 6-(ptolyl)pyridazin-3(2H)-one (5), 0.02 mol (2.2252 mL) ethyl bromopropionate, and 0.02 mol (2.7636 g) potassium carbonate were refluxed. After cooling, the organic salts were filtered out, the solvent was removed, and the residue was refined by recrystallization with methanol to get the esters [15].…”

“…Pyridazinone derivatives have been suggested to offer such intriguing bioactivity as an antitumoral, antibacterialantifungal, anticonvulsant, analgesic, anti-inflammatory, antiplatelet, and anticancer impact [5][6][7][8][9][10][11][12]. Also, many of the pyridazinone derivatives have been synthesized by our research group as an inhibitor of cholinesterases which are from the serine hydrolase enzyme family [13][14][15][16][17]. It has been reported that compounds with heterocyclic ring containing nitrogen and oxygen atoms, such as oxadiazolone, benzo [1,3]oxazinon and benzoxazole, inhibit PLL.…”