- Development of novel 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives as balanced multifunctional agents against Alzheimer's disease
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Based on multitarget-directed ligands approach, through two rounds of screening, a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives were designed, synthesized and evaluated as innovative multifunctional agents against Alzheimer's disease. In vitro biological assays indicated that most of the hybrids were endowed with great AChE inhibitory activity, excellent antioxidant activity and moderate Aβ1-42 aggregation inhibition. Taken both efficacy and balance into account, 12a was identified as the optimal multifunctional ligand with significant inhibition of AChE (EeAChE, IC50 = 0.20 μM; HuAChE, IC50 = 37.02 nM) and anti-Aβ activity (IC50 = 1.92 μM for self-induced Aβ1-42 aggregation; IC50 = 1.80 μM for disaggregation of Aβ1-42 fibrils; IC50 = 2.18 μM for Cu2+-induced Aβ1-42 aggregation; IC50 = 1.17 μM for disaggregation of Cu2+-induced Aβ1-42 fibrils; 81.7% for HuAChE-induced Aβ1-40 aggregation). Moreover, it was equipped with the potential to serve as antioxidant (3.03 Trolox equivalents), metals chelator and anti-neuroinflammation agent for synergetic treatment. Finally, in vivo study demonstrated that 12a, with suitable BBB permeability (log BB = ?0.61), could efficaciously ameliorate cognitive dysfunction on scopolamine-treated mice by regulating cholinergic system and oxidative stress simultaneously. Altogether, these results highlight the potential of 12a as an innovative balanced multifunctional candidate for Alzheimer's disease treatment.
- Shi, Yichun,Zhang, Heng,Song, Qing,Yu, Guangjun,Liu, Zhuoling,Zhong, Feng,Tan, Zhenghuai,Liu, Xiuxiu,Deng, Yong
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- One-pot preparation of 6-substituted 3(2H)-pyridazinones from ketones
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A one-pot process for the preparation of 6-phenyl-3(2H)-pyridazinone from acetophenone and glyoxylic acid has been investigated and shown to have wide utility in the preparation of 6- and 5,6-substituted 3(2H)-pyridazinones. Limitations to the process encountered with 2'-hydroxyacetophenone and with basic hetero-aromatic ketones have been overcome, and the processes described offer the rapid and efficient synthesis of many 6-substituted pyridazinones from readily available ketones.
- Coates,McKillop
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p. 334 - 342
(2007/10/02)
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- Process for preparing 6-(2-hydroxyphenyl)-3-pyridazinone
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A process for preparing 6-(2-hydroxyphenyl)-3-pyridazinone which comprises reacting 2-hydroxyacetophenone with glyoxylic acid under alkaline conditions, adjusting the pH of the reaction mixture to give a mixture within a pH range of about pH 4.0-9.5 and which contains a weak base, and subsequently reacting with hydrazine. 6-(2-Hydroxyphenyl)-3-pyridazinone is a useful intermediate in the preparation of anti-hypertensive agents.
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- Intermediates for preparing hydroxyphenylpyridazinones
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5-(5'-Halo-2'-methoxyphenyl)-3,4-dihalo-2(5H)-furanones are prepared by a Friedel-Crafts reaction using a p-haloanisole and a mucohalic acid in the presence of aluminum chloride. They are used as chemical intermediates for preparing hydroxyphenylpyridazinones.
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- 1,1,1-Trihalo-2-hydroxy-4-(2-hydroxyphenyl)-4-butanones
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A new synthesis for the preparation of 6-(2-hydrophenyl)-3-pyridazinones whose key reaction is cyclizing a 1,1,1-trihalo-2-hydroxy-4-(2-hydroxyphenyl)-4-butanone with hydrazine. 6-(2-Hydroxyphenyl)-3-pyridazinones are important intermediates for preparing medicinally active compounds especially 3-[2-(3-tert.-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine or its nontoxic acid addition salts. The invention claimed here is the trihalocarbinol intermediates.
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- 3-Chloro-6-phenylpyridazine compounds
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Substituted derivatives of 3-chloro-6-phenylpyridazine which are useful intermediates in the preparation of substituted phenylhydrazinopyridazines which have β-adrenergic blocking and vasodilator activity.
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