Abstract
BackgroundThe study aimed to design, synthesize and evaluate various brominated derivatives of 7-hydroxy coumarin as a new scaffold against Alzheimer’s disease by in vivo and in vitro models. A group of three novel pyrazoles endowed with brominated 7-hydroxy 4-methyl coumarin derivatives were designed. Among the designed compounds, a single entity (D1) was selected based on the docking score, which could be considered mainly for the treatment of Alzheimer’s disease. Three novel pyrazoles endowed with brominated 7-hydroxy 4-methyl coumarin derivatives were designed and docking studies of these compounds were carried out using Argus lab4.0.1 version. According to the docking score, a single entity of compound (D1) was selected for further study. The structure of the compound (D1) was explored by spectral analysis. The anti-Alzheimer’s activity was evaluated by in vivo and in vitro methods. All results were compared statistically by one-way ANOVA using GraphPad Prism.ResultsMolecular docking studies revealed that the compound D1 was able to bind simultaneously to the amino acid and in the active sites of the acetylcholine esterase enzyme. In acetylcholine esterase inhibition assay, the compound shows a significant increase in acetylcholine esterase level. The MAO inhibitory activities were in the nanomole range (human MAO-A IC50 = 3.9, human MAO-B IC 50 = 4.4). DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assay showed that the compound shows a promising antioxidant property. In the evaluation of learning and memory of compound D1 using elevated plus maze, the compound D1-pretreated group showed a significant increase in memory and learning when compared with donepezil.ConclusionsAmong the designed series of pyrazole endowed with brominated 7-hydroxyl 4-methyl coumarin derivatives, compound D1 showed good antioxidant property and acetylcholine esterase and MAO inhibitory activity; based on this property, the synthesized compound D1 can be considered a new scaffold on Alzheimer’s disease.
Highlights
The study aimed to design, synthesize and evaluate various brominated derivatives of 7-hydroxy coumarin as a new scaffold against Alzheimer’s disease by in vivo and in vitro models
The docking results showed that all derivatives have an almost similar binding mode with different docking scores
Synthesis of compound D1 Based on the docking score, compound D1 showed a strong affinity towards the target enzyme acetylcholine esterase
Summary
The 3 designed compounds (Table 1) were subjected to docking via the Argus Lab docking software. The docking results showed that all derivatives have an almost similar binding mode with different docking scores. Compound D1 ( see Fig. 1) was synthesized by the reaction of 7-hydroxy -4-methyl coumarin with potassium bromide and potassium bromate solution to form 3-bromo-7-hydroxy-4 methyl-2H-chromen-2-one (Scheme 1) is converted to ethyl[(3-bromo-4-methyl-2oxo-2H-chromen-7-yl)oxy]acetate in the presence of ethyl chloroacetate (Scheme 2), which reacts with hydrazine hydrate in ethanol afforded 2-(4-methyl-2-oxo-2H chromen-7-yloxy) acetohydrazide (Scheme 3). The reaction of this hydrazide with pyrazolone leads to the.
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