- Synthesis and Anti-neuroinflammatory Activity of Lactone Benzoyl Hydrazine and 2-nitro-1-phenyl-1H-Indole Derivatives as p38α MAPK Inhibitors
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Inhibition of p38 mitogen-activated protein kinases (MAPKs) would allow significant modulation of the neuroinflammation condition associated with Alzheimer's disease (AD). Inspired from the pharmacophore of natural NF-κB and p38α MAPK inhibitor 5,6-dehydrokawain and p38α MAPK inhibitors 1a, 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl)ureas, and 1b, a class of indole-pyrimidinyl compounds which were patented respectively, we designed, de novo synthesized, and evaluated two kinds of novel series of lactone benzoyl hydrazine derivatives and 2-nitro-1-phenyl-1H-indole derivatives in an effort to develop pharmacologically tractable agents to alleviate the progression of AD. Fourteen of the seventeen synthesized compounds exhibit significant inhibitory effect on the nitric oxide (NO) production induced by lipopolysaccharide (LPS)-induced microglia activation with IC50 less than the control 5,6-dehydrokawain. Notably, compound 27, 6-methoxy-2-nitro-1-(1H-1, 2, 3-triazol-1-yl)-1H-indole, with IC50 values of 1.6 μm can markedly inhibit p38α MAPK and NO release in BV-2 microglial cells. The molecular dynamic (MD) simulations demonstrate that compound 27 inhibits p38α MAPK through binding to the Glu71 and Asp168 residues. Moreover, in vitro study shows that all compounds can easily cross the blood-brain barrier (BBB) and did not exhibit any acute cellular toxicity checked by MTT assay. These investigations provide promising chemical lead candidate as anti-neuroinflammatory agents for AD. We designed, synthesized and evaluated two series lactone benzoyl hydrazine and 2-nitro-1-phenyl-1H-Indole derivatives for novel promising chemical lead p38α MAPK inhibitors as anti-neuroinflammatory agents in fighting against Alzheimer's diseases.
- Cheng, Bao,Lin, Yongsheng,Kuang, Ming,Fang, Sai,Gu, Qiong,Xu, Jun,Wang, Laiyou
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- Regio- and Stereoselective Cascade of β,γ-Unsaturated Ketones by Dipeptided Phosphonium Salt Catalysis: Stereospecific Construction of Dihydrofuro-Fused [2,3-b] Skeletons
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Chiral (dihydro)furo-fused heterocycles are significant structural motifs in numerous natural products, functional materials and pharmaceuticals. Therefore, developing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein, we develop an effective, modular method by a dipeptide-phosphonium salt-catalyzed regio- and stereoselective cascade reaction of readily available linear β,γ-unsaturated ketones with aromatic alkenes, affording a wide variety of structurally fused heterocyclic molecules in high yields with excellent stereoselectivities. Moreover, mechanistic investigations revealed that the bifunctional phosphonium salt controlled the regio- and stereoselectivities of this cascade reaction, particularly proceeding through the initial ketone α-addition followed by O-participated substitution; and the multiple hydrogen-bonding interactions between Br?nsted acid moieties of catalyst and nitro group of aromatic alkene were crucial in asymmetric induction. Given the generality, versatility, and high efficiency of this method, we anticipate that it will have broad synthetic utilities.
- Chen, Yayun,He, Jiajia,Jiang, Chunhui,Ren, Xiaoyu,Su, Zhishan,Wang, Tianli,Xiao, Kai,Zhang, Hongkui,Zhuang, Cheng
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p. 19860 - 19870
(2021/08/06)
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- Strategies towards potent trypanocidal drugs: Application of Rh-catalyzed [2?+?2?+?2] cycloadditions, sulfonyl phthalide annulation and nitroalkene reactions for the synthesis of substituted quinones and their evaluation against Trypanosoma cruzi
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Rhodium-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulations and nitroalkene reactions have been employed for the synthesis of 56 quinone-based compounds. These were evaluated against Trypanosoma cruzi, the parasite that causes Chagas disease. The reactions described here are part of a program that aims to utilize modern, versatile and efficient synthetic methods for the one or two step preparation of trypanocidal compounds. We have identified 9 compounds with potent activity against the parasite; 3 of these were 30-fold more potent than benznidazole (Bz), a drug used for the treatment of Chagas disease. This article provides a comprehensive outline of reactions involving over 120 compounds aimed at the discovery of new quinone-based frameworks with activity against T. cruzi.
- Wood, James M.,Satam, Nishikant S.,Almeida, Renata G.,Cristani, Vinicius S.,de Lima, Dênis P.,Dantas-Pereira, Luiza,Salom?o, Kelly,Menna-Barreto, Rubem F.S.,Namboothiri, Irishi N.N.,Bower, John F.,da Silva Júnior, Eufranio N.
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- Asymmetric dearomatization of 2-nitrobenzofurans by organocatalyzed one-step Michael addition to access 3,3′-disubstituted oxindoles
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An efficient enantioselective dearomatization of 2-nitrobenzofurans was realized via an organocatalyzed one-step Michael addition process. This method provides a facile strategy to access a range of structurally diverse 3,3′-disubstituted oxindoles, which feature an intriguing combination of two privileged motifs including 3-pyrrolyl-substituted-oxindoles and 2,3-dihydrobenzofurans substructures, in excellent results.
- Ge, Zhen-Zhen,Wang, Zhen-Hua,Xie, Ke-Xin,Yang, Lei,You, Yong,Yuan, Wei-Cheng,Zhao, Jian-Qiang,Zhou, Ming-Qiang
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p. 2586 - 2589
(2020/03/10)
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- Phosphine-Catalyzed Enantioselective Dearomative [3+2]-Cycloaddition of 3-Nitroindoles and 2-Nitrobenzofurans
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Over the past years, the metal-catalyzed dearomative cycloaddition of 3-nitroindoles and 2-nitrobenzofurans have emerged as a powerful protocol to construct chiral fused heterocyclic rings. However, organocatalytic dearomative reaction of these two classe
- Wang, Huamin,Zhang, Junyou,Tu, Youshao,Zhang, Junliang
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p. 5422 - 5426
(2019/03/17)
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- Facile synthesis of chiral [2,3]-fused hydrobenzofuran: Via asymmetric Cu(i)-catalyzed dearomative 1,3-dipolar cycloaddition
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Intermolecular asymmetric dearomative 1,3-dipolar cycloaddition of 2-nitrobenzofurans with azomethine ylides was enabled by using a chiral Cu(i)/(S,Sp)-iPr-Phosferrox catalyst. As a result, a series of highly stereoselective chiral [2,3]-fused hydrobenzofurans possessing four contiguous stereogenic centers were obtained with good to high yields, diastereoselectivities and enantioselectivities. The reaction has broad substrate scope tolerating various functional groups.
- Liang, Lei,Niu, Hong-Ying,Wang, Dong-Chao,Yang, Xin-He,Qu, Gui-Rong,Guo, Hai-Ming
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p. 553 - 556
(2019/01/10)
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- Enantioselective dearomative [3+2] cycloaddition of 2-nitrobenzofurans with aldehyde-derived Morita-Baylis-Hillman carbonates
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The phosphine-catalyzed asymmetric dearomative [3+2] cycloaddition of 2-nitrobenzofurans with aldehyde-derived Morita-Baylis-Hillman (MBH) carbonates or allenoate was developed. The reaction with MBH carbonates resulted in a series of cyclopentabenzofurans containing three contiguous stereocenters with good to high yields, diastereoselectivities and enantioselectivities. The use of allenoate also gave the target product with moderate enantioselectivity.
- Yang, Xin-He,Li, Jian-Ping,Wang, Dong-Chao,Xie, Ming-Sheng,Qu, Gui-Rong,Guo, Hai-Ming
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p. 9144 - 9147
(2019/08/07)
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- Palladium(0)-Catalyzed Dearomatization of 2-Nitrobenzofurans through Formal (3+2) Cycloadditions with Vinylcyclopropanes: A Straightforward Access to Cyclopenta[ b ]benzofurans
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In the context of the palladium-catalyzed dearomatization of electron-poor arenes, we report herein that various 2-nitrobenzofurans efficiently undergo a dearomative (3+2) cycloaddition with vinylcyclopropanes. This new method gives access to a wide variety of cyclo-penta[ b ]benzofuran derivatives in a straightforward manner.
- Ling, Johanne,Laugeois, Maxime,Michelet, Véronique,Ratovelomanana-Vidal, Virginie,Vitale, Maxime R.
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supporting information
p. 928 - 932
(2018/02/14)
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- Palladium-Catalyzed Highly Stereoselective Dearomative [3 + 2] Cycloaddition of Nitrobenzofurans
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Stereoselective construction of highly functionalized heterocyclic molecules is an ongoing concern for the chemical community. Among the various strategies developed with this goal, catalytic asymmetric dearomatization, an attractive method for constucting cyclic molecules with multiple stereocenters from readily available aromatic compounds, has received extensive attention in recent years. Here, we report a highly stereoselective construction of tetrahydrofurobenzofurans and tetrahydrofurobenzothiophenes via palladium-catalyzed dearomative [3 + 2] cycloaddition of nitrobenzofurans and nitrobenzothiophenes, respectively. Good to excellent yields (63%–92%), diastereoselectivity (13/1 → >20/1 dr), and enantioselectivity (75%–95% ee) were obtained, leading to products with vicinal stereogenic carbon centers. The reaction features wide substrate scope and diverse transformations of the products.
- Cheng, Qiang,Zhang, Hui-Jun,Yue, Wen-Jun,You, Shu-Li
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p. 428 - 436
(2017/09/22)
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- Potassium trinitromethanide as a 1,1-ambiphilic synthon equivalent: Access to 2-nitroarenofurans
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The first example of the use of potassium trinitromethanide as a 1,1-ambiphilic synthon equivalent for the construction of a benzofuran moiety mediated by triethylamine has been developed. The method tolerates a variety of functional groups on the starting quaternary ammonium salt and has been successfully extended to polysubstituted benzofurans. Formation of an o-quinone methide intermediate is postulated as a key to the mechanism of this cascade process.
- Osyanin, Vitaly A.,Osipov, Dmitry V.,Demidov, Maxim R.,Klimochkin, Yuri N.
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p. 1192 - 1198
(2014/03/21)
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- An Improved Synthesis of 2-Nitrobenzofurans
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2-Nitrobenzofurans 4 are prepared in improved yields by reacting o-hydroxybenzaldehydes 1 and bromonitromethane (2) at low temperature in order to avoid the dehydration of the aldol intermediate 3 in the alkaline condensation medium.This aldol 3 is then quantitatively dehydrated by heating in acetic anhydride.
- Tromelin, Anne,Demerseman, Pierre,Royer, Rene
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p. 1074 - 1076
(2007/10/02)
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- Reactions of Salicylaldehydes with Bromonitromethane
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Various salicylaldehydes were treated with bromonitromethane in the presence of an inorganic base to give 2-nitrobenzofuran derivatives, and the reaction mechanisms were investigated.The most remarkable feature of the reactions is that 3-hydroxysalicylaldehyde (1k) alone among various hydroxysalicylaldehydes (1b, k, n, r) gave 2-nitro-7-hydroxybenzofuran in good yield.Bromonitromethane reacted with salicylaldehydes at the aldehyde group exclusively to give 1-(2-hydroxyphenyl)-2-bromo-2-nitroethanols (14), followed by cyclization to produce mixtures consisting of cis- and trans-2-nitro-3-hydroxy-2,3-dihydrobenzofurans (8a, b; 9a, b; 10a, b).The stereochemistry of these products is discussed on the basis of the spectral data and chemical reactivities.The intermediates, 2,3-dihydrobenzofurans, underwent dehydration smoothly to give 2-nitrobenzofurans.Keywords - bromonitromethane; salicylaldehyde derivative; ring closure; 2-nitrobenzofuran derivative; cis-2-nitro-3-hydroxy-2,3-dihydrobenzofuran derivative; trans-2-nitro-3-hydroxy-2,3-dihydrobenzofuran derivative; 13C-NMR; stereochemistry; reaction mechanism
- Ohishi, Yoshitaka,Doi, Yoshio,Nakanishi, Teruo
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p. 4260 - 4270
(2007/10/02)
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