- Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors
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There has been a substantial research effort to design multi-target ligands for the treatment of Alzheimer's disease (AD), an approach that is moved by the knowledge that AD is a complex and multifactorial disease affecting many linked to pathological pathways. Accordingly, we have devoted efforts to develop multi-target ligands based on the chromone scaffold. As a result, a small library of chromone derivatives was synthesized and screened towards human cholinesterases and monoamine oxidases. Compounds 2-(dimethylamino)ethyl (E)-3-(4-oxo-2-(p-methylphenlcarbamoyl)-4H-chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4H-chromen-6-yl)acrylate (23a) were identified as the most promising multi-target inhibitors of the series. Compound 9a acted as a potent, selective and bifunctional AChEI (IC50 = 0.21 μM, Ki = 0.19 μM) and displayed dual hMAO inhibitory activity (hMAO-A IC50 = 0.94 μM, Ki = 0.057 μM and hMAO-B IC50 = 3.81 μM, Ki = 0.48 μM). Compound 23a acted as a selective IMAO-B (IC50 = 0.63 μM, Ki = 0.34 μM) while still displaying hChE inhibitory and bifunctional activity in the low micromolar range. Overall, these two compounds stand out as reversible multi-target inhibitors with favourable permeability, toxicological and drug-like profiles, thus being valid candidates for subsequent optimization and pre-clinical studies.
- Reis, Joana,Cagide, Fernando,Valencia, Martín Estrada,Teixeira, José,Bagetta, Donatella,Pérez, Concepción,Uriarte, Eugenio,Oliveira, Paulo J.,Ortuso, Francesco,Alcaro, Stefano,Rodríguez-Franco, María Isabel,Borges, Fernanda
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- Chromone and donepezil hybrids as new multipotent cholinesterase and monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease
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A series of chromone and donepezil hybrids were designed, synthesized, and evaluated as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential therapy of Alzheimer's disease (AD). In vitro studies showed that the great majority of these compounds exhibited potent inhibitory activity toward BuChE and AChE and clearly selective inhibition for hMAO-B. In particular, compound 5c presented the most balanced potential for ChE inhibition (BuChE: IC50 = 5.24 μM; AChE: IC50 = 0.37 μM) and hMAO-B selectivity (IC50 = 0.272 μM, SI = 247). Molecular modeling and kinetic studies suggested that 5c was a mixed-type inhibitor, binding simultaneously to peripheral and active sites of AChE. It was also a competitive inhibitor, which occupied the substrate and entrance cavities of MAO-B. Moreover, compound 5c could penetrate the blood-brain barrier (BBB) and showed low toxicity to rat pheochromocytoma (PC12) cells. Altogether, these results indicated that compound 5c might be a hopeful multitarget drug candidate with possible impact on Alzheimer's disease therapy.
- Huang, Ming,Jiang, Neng,Kong, Ling-Yi,Lan, Jin-Shuai,Wang, Xiao-Bing,Yin, Fu-Cheng
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p. 225 - 233
(2020/04/22)
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- Synthesis and biological evaluation of chromone-3-carboxamides
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The aim of our study was to synthesize novel chromone-3-carboxamides and to conduct biological evaluations in search for lead compounds for the treatment of a range of debilitating disease states. Corresponding 2-hydroxyacetophenones were subjected to Vilsmeier-Haack formylation to give chromone-3-carbaldehydes, which were subsequently oxidised to give chromone-3-carboxylic acids. Treatment of the carboxylic acids with thionyl chloride resulted in the in situ formation of the corresponding acid chlorides, which were reacted with various amines in the presence of triethylamine to give the corresponding novel chromone-3-carboxamides in good yields. Selected chromone derivatives were then evaluated for their anti-inflammatory, anti-tryponosomal and cytotoxic properties.
- Gordon, Allen T.,Ramaite, Isaiah D.I.,Mnyakeni-Moleele, Simon S.
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p. 148 - 160
(2021/01/20)
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- Synthesis of 3-(3-alkyl-5-thioxo-1H-4,5-dihydro-1,2,4-triazol-4-yl) aminocarbonylchromones
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A series of 3-(3-alkyl-5-thioxo-1H-4,5-dihydro-1,2,4-triazol-4-yl) aminocarbonylchromones has been prepared by oxidation of 3-formylchromone with Jones' reagent followed by reaction with 3-alkyl-4-amino-4,5-dihydro-1,2,4- triazole-5(1H)-thione in the presence of POCl3. The structures of the compounds were confirmed by IR, LC-MS, and 1H NMR spectra and elemental analyses.
- Cao, Linghua,Zhang, Lin,Cui, Pengyuan
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p. 635 - 640
(2007/10/03)
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- Kinetics and mechanism of hydrogen peroxide oxidation of chromone-3-carboxaldehydes in aqueous acid and micellar media
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Oxidation of chromone-3-carboxaldehyde (CCA) and substituted analogues by H2O2 has been carried out in aqueous acid (HCl and H2SO4) and micellar media. Reaction kinetics indicated order in |CCA| as well as |H2O2| to be unity while it is a fraction (1 > n > O) in |acid|. Reaction rates were found to be faster in the solvents of low-dielectric constant (D). Added salt (KCl or (NH4)2SO4) increased the rate of oxidation marginally. On the basis of observed linearity of Amis plot and marginal positive salt effect, protonated CCA (enol form of CCA, a cation) and H2O2 (neutral molecule) were considered as reactive species in the rate limiting step. Reaction rates were found to be enhanced significantly in anionic and nonionic micellar (sodium dodecylsulfate (SDS) and Triton X-100 (Tx), respectively) media. However, cationic micelles [cetyl trimethyl ammonium bromide (CTAB)| indicated marginal retardation effect. Effect of anionic and cationic micelles has been interpreted in terms of electrostatic interactions, while that of nonionic micelles in terms of hydrophobic interactions. Structure-reactivity correlations have been interpreted by Hammett's equation. Negative "p" (reaction constant) values indicated cationic transition state. 1996 John Wiley &Sons, Inc.
- Matha,Sundari,Rajanna,Saprakash
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p. 637 - 648
(2007/10/03)
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