- The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation
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Adenylate cyclases (ACs), play a critical role in the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP). Studies have indicated that adenylyl cyclase type 2 (AC2) is potential drug target for many diseases, however, up to now, there is no AC2-selective agonist reported. In this research, docking-based virtual screening with the combination of cell-based biological assays have been performed for discovering novel potent and selective AC2 agonists. Virtual screening disclosed a novel hit compound 8 as an AC2 agonist with EC50 value of 8.10 μM on recombinant human hAC2 + HEK293 cells. The SAR (structure activity relationship) based on the derivatives of compound 8 was further explored on recombinant AC2 cells and compound 73 was found to be the most active agonist with the EC50 of 90 nM, which is 160-fold more potent than the reported agonist Forskolin and could selectively activate AC2 to inhibit the expression of Interleukin-6. The discovery of a new class of AC2-selective agonists would provide a novel chemical probe to study the physiological function of AC2.
- Li, Shanshan,Song, Gao,Wang, Liang-Liang,Weng, Zhiying,Xu, Guowei,Yang, Weimin,Yang, Yanming,Yang, Yaqing,Zhang, Jiajun,Zuo, Zhili
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supporting information
(2020/02/27)
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- Design, synthesis and biological evaluation of novel 3,4-dihydro-2(1H)-quinolinone derivatives as potential chitin synthase inhibitors and antifungal agents
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A series of 3,4-dihydro-2(1H)-quinolinone derivatives contained butenediamide fragment were designed and synthesized. Their inhibition potency against chitin synthase and antimicrobial activities were screened in vitro. The enzymatic assays showed that all the synthesized compounds had inhibition potency against chitin synthase at concentration of 300 μg/mL. Compound 2d displayed excellent potency with inhibition percentage (IP) value of 82.3%, while IP value of the control polyoxin B was 87.5%. Compounds 2b, 2e and 2s whose IP values were above 70% showed good inhibition potency against chitin synthase. Moreover, the IC50 value of 2b was comparable with that of polyoxin B (0.09 mM). The Ki of compound 2b was 0.12 mM and the result from Lineweaver-Burk plot showed that 2b was non-competitive inhibitor to bind chitin synthase. The antifungal experiment showed that these compounds had excellent antifungal activity against fungal strains, especially for candida albicans. The antifungal activities against C .albicans of compounds 2b, 2d, 2e and 2l were comparable with that of fluconazole and were superior to that of polyoxin B. Meanwhile, the other compounds against C. albicans showed better antifungal activity (MIC 2 μg/mL) than polyoxin B except for compound 2n (MIC 4 μg/mL). The trial of drug combination use showed that these synthesized compounds had synergistic effects with fluconazole and polyoxin B. It indicated that these compounds were not competing with polyoxin B to bind with chitin synthase, which was also consistence with the result of enzymatic assays. The antibacterial experiment showed that these compounds had no activity against selected strains including three Gram-positive and three Gram-negative bacteria. These results showed that the designed compounds were chitin synthase inhibitors and had selective antifungal activity.
- Ji, Qinggang,Li, Baihui,Shen, Yangli,Wu, Hu,Wu, Xiaobo,Yuan, Lvjiang
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- Alizarin red S-TiO2-catalyzed cascade C(sp3)-H to C(sp2)-H bond formation/cyclization reactions toward tetrahydroquinoline derivatives under visible light irradiation
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A very low amount of organic dye (Alizarin red S) sensitized TiO2 and it was successfully used to catalyze cascade C(sp3)-H to C(sp2)-H bond formation/cyclization reactions under visible light irradiation. The modified TiO2 photocatalyst efficiently, for the first time, advanced [4+2] cyclization of N,N-dimethylanilines and maleimides to the corresponding tetrahydroquinolines in air atmosphere. The reaction proceeds through α-amino radicals without additional oxidant at ambient temperature to afford products in good to excellent yields.
- Hosseini-Sarvari, Mona,Koohgard, Mehdi,Firoozi, Somayeh,Mohajeri, Afshan,Tavakolian, Hosein
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supporting information
p. 6880 - 6888
(2018/05/04)
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- Three-Component Synthesis of Quinolines Based on Radical Cascade Visible-Light Photoredox Catalysis
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Synthesis of highly substituted quinolines has been developed based on three-component radical cascade based on visible-light photoredox catalysis. This tandem coupling reaction has been coordinated to proceed with high chemoselectivity based on the differential electronic properties of coupling partners. Subjection of electron-rich β-aminoacrylates with electron-deficient halides and alkenes to the optimized conditions leads to the formation of quinolines in good yields after in situ oxidation of tetrahydroquinolines. Detailed mechanistic studies which reveal an unexpected reaction pathway is described. (Figure presented.).
- Choi, Jun-Ho,Park, Cheol-Min
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supporting information
p. 3553 - 3562
(2018/09/22)
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- Catalyst and Additive-Free Diastereoselective 1,3-Dipolar Cycloaddition of Quinolinium Imides with Olefins, Maleimides, and Benzynes: Direct Access to Fused N,N′-Heterocycles with Promising Activity against a Drug-Resistant Malaria Parasite
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A convenient and eco-friendly synthesis of various fused N-heterocyclic compounds through catalyst and additive-free 1,3 dipolar cycloadditions of quinolinium imides with olefins, maleimides, and benzynes in excellent yields and diastereoselectivities is reported. The thermally controlled diastereoselective [3 + 2] cycloaddition reaction between quinolinium imides and olefins provided cis-isomers at low temperature and trans-isomers at high temperature. A reaction between quinolinium imides with substituted maleimides gave four-ring-fused N-heterocyclic compounds in high yields as a single diastereomer. The aryne precursors also provided four-ring-fused N,N′-heterocyclic compounds in high yields. The in vitro antiplasmodial activity of selected molecules revealed that this class of molecules possesses potential for ongoing studies against malaria.
- Kumar, Rakesh,Chaudhary, Sandeep,Kumar, Rohit,Upadhyay, Pooja,Sahal, Dinkar,Sharma, Upendra
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p. 11552 - 11570
(2018/09/25)
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- Solvent-free and room temperature visible light-induced C-H activation: CdS as a highly efficient photo-induced reusable nano-catalyst for the C-H functionalization cyclization of: T -amines and C-C double and triple bonds
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Nano-sized CdS was successfully prepared, fully characterized and applied as a highly efficient reusable photocatalyst for the synthesis of pyrrolo[3,4-c]quinolone and pyrrolo[2,1-a]isoquinoline-8-carboxylate derivatives through a condensation reaction of N,N-dimethylanilines or alkyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)acetates with maleimides via a C-H activation approach under benign and eco-friendly conditions at room temperature without using any solvent and oxidant under visible light irradiation. Besides, the prepared photocatalyst has been successfully applied for the condensation reaction of N,N-dimethylanilines with alkyl but-2-ynedioates or phenyl acetylenes for the synthesis of novel 1,2-dihydroquinoline-3,4-dicarboxylate and aryl-1,2-dihydroquinoline derivatives for the first time. Using this method, all favourable products were obtained in good yields and relatively short reaction times under benign conditions with the application of visible light irradiation, a renewable energy source. The catalyst was easily recovered and reused several times without any loss of its activity.
- Firoozi, Somayeh,Hosseini-Sarvari, Mona,Koohgard, Mehdi
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supporting information
p. 5540 - 5549
(2019/01/03)
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- Potent Nematicidal Activity of Maleimide Derivatives on Meloidogyne incognita
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Different maleimide derivatives were synthesized and assayed for their in vitro activity on the soil inhabiting, plant-parasitic nematode Meloidogyne incognita, also known as root-knot nematode. The compounds maleimide, N-ethylmaleimide, N-isopropylmaleimide, and N-isobutylmaleimide showed the strongest nematicidal activity on the second stage juveniles of the root-knot nematode with EC50/72h values of 2.6 ± 1.3, 5.1 ± 3.4, 16.2 ± 5.4, and 19.0 ± 9.0 mg/L, respectively. We also determined the nematicidal activity of copper sulfate, finding an EC50 value of 48.6 ± 29.8 mg/L. When maleimide at 1 mg/L was tested in combination with copper sulfate at 50 mg/L, we observed 100% mortality of the nematodes. We performed a GC-MS metabolomics analysis after treating nematodes with maleimide at 8 mg/L for 24 h. This analysis revealed altered fatty acids and diglyceride metabolites such as oleic acid, palmitic acid, and 1-monopalmitin. Our results suggest that maleimide may be used as a new interesting building block for developing new nematicides in combination with copper salts.
- Eloh, Kodjo,Demurtas, Monica,Mura, Manuel Giacomo,Deplano, Alessandro,Onnis, Valentina,Sasanelli, Nicola,Maxia, Andrea,Caboni, Pierluigi
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p. 4876 - 4881
(2016/07/06)
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- Visible light mediated cyclization of tertiary anilines with maleimides using nickel(II) oxide surface-modified titanium dioxide catalyst
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Surface-modified titanium dioxides by highly dispersed NiO particles have an extended absorption in the visible light region and a reduced hole-electron pair recombination than unmodified TiO2. They have now been successfully applied as highly active heterogeneous photocatalysts in the visible light mediated direct cyclization of tertiary anilines with maleimides to give tetrahydroquinoline products in moderate to high yields at ambient temperature. In contrast with unmodified titanium dioxide catalysts that are conventionally used in a stoichiometric amount in combination with UVA light, only a catalytic amount (1 mol %) of the surface-modified TiO2 catalyst is needed along with visible light to efficiently catalyze the reaction. Compared with transition-metal complexes such as Ru(bpy)3Cl2 or Ir(ppy)2(dtbbpy)PF6, advantages of these surface-modified titanium dioxides as photocatalyst include high catalytic activity, low cost, ease of recovering, and being able to be used for at least nine times without significant decay of catalytic activity.
- Tang, Jian,Grampp, Günter,Liu, Yun,Wang, Bing-Xiang,Tao, Fei-Fei,Wang, Li-Jun,Liang, Xue-Zheng,Xiao, Hui-Quan,Shen, Yong-Miao
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supporting information
p. 2724 - 2732
(2015/03/18)
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- Study of the diels-alder and retro-diels-alder reaction between furan derivatives and maleimide for the creation of new materials
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The Diels-Alder reaction leads to a mixture of two diastereomers, one called endo and the other one exo. The cyclo-reversion temperature of the first one is lower than the exo adduct and the ratio between endo and exo adducts varies according to the substituents of the Diels-Alder partners and experimental parameters. Therefore, the influence of some reaction parameters such as the substituents of furan and maleimide derivatives, the reaction temperature and the presence of a nucleophile on the endo/exo Diels-Alder ratio and/or the retro-Diels-Alder reaction have been studied. For instance, furan and maleimide derivatives with electron withdrawing substituents induced the creation of the endo adduct preferentially. Also the presence of a far electron withdrawing substituent on furan and/or an electron attracting mesomeric substituent on maleimide resulted in a faster reversibility of the endo adduct. Finally, a high temperature and the presence of a nucleophile (thiol) also induced faster retro-Diels-Alder kinetics. Moreover, it was proved that isomerization from the endo to the exo diastereomer is preceded by a retro-Diels-Alder reaction of the endo adduct. The presence of a nucleophile in the mixture confirmed this result. This study allowed the highlighting of different parameters of the Diels-Alder reaction to obtain as much endo adduct as possible, and a fast and/or full retro-Diels-Alder reaction of this adduct.
- Froidevaux,Borne,Laborbe,Auvergne,Gandini,Boutevin
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p. 37742 - 37754
(2015/05/13)
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- Copper-phenanthroline catalysts for regioselective synthesis of pyrrolo[3′,4′:3,4]pyrrolo[1,2-a]furoquinolines/phenanthrolines and of pyrrolo[1,2-a]phenanthrolines under mild conditions
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A new series of pyrrolo[3′,4′:3,4]pyrrolo[1,2-a]furoquinolines/ phenanthrolines and pyrrolo[1,2-a]phenanthrolines were efficiently built up from an 8-hydroxyquinoline derivative or phenanthroline via 1,3-dipolar cycloaddition reaction involving non-stabilized azomethine ylides, generated in situ from the parent furo[3,2-h]quinoliniums/phenanthroliums, in presence of a copper(II) chloride-phenanthroline catalytic system. The methodology combines general applicability with high yields.
- Paira, Rupankar,Anwar, Tarique,Banerjee, Maitreyee,Bharitkar, Yogesh P.,Mondal, Shyamal,Kundu, Sandip,Hazra, Abhijit,Maulik, Prakas R.,Mondal, Nirup B.
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supporting information
p. 692 - 700
(2014/04/17)
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- Chemical reactivity and antimicrobial activity of N-substituted maleimides
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Several N-substituted maleimides containing substituents of varying bulkiness and polarity were synthesised and tested for antimicrobial and cytostatic activity. Neutral maleimides displayed relatively strong antifungal effect minimum inhibitory concentrations (MICs in the 0.54 g ml-1 range); their antibacterial activity was structure dependent and all were highly cytostatic, with IC50 values below 0.1 g ml-1. Low antimicrobial but high cytostatic activity was noted for basic maleimides containing tertiary aminoalkyl substituents. Chemical reactivity and lipophilicity influenced antibacterial activity of neutral maleimides but had little if any effect on their antifungal and cytostatic action. N-substituted maleimides affected biosynthesis of chitin and β(1,3)glucan, components of the fungal cell wall. The membrane enzyme, β(1,3)glucan synthase has been proposed as a putative primary target of N-ethylmaleimide and some of its analogues in Candida albicans cells.
- Salewska, Natalia,Boros-Majewska, Joanna,Lcka, Izabela,Chylinska, Katarzyna,Sabisz, Michal,Milewski, Slawomir,Milewska, Maria J.
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scheme or table
p. 117 - 124
(2012/04/18)
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- Total synthesis of (±)-dysibetaine CPa and analogs
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The syntheses of the marine sponge-derived γ-amino carboxylic acid dysibetaine CPa and five analogs in their racemic forms were successfully performed by taking advantage of an electron-withdrawing N-(4-nitrophenyl) group in the cyclopropanation reaction,
- Oikawa, Masato,Sasaki, Shota,Sakai, Michihiro,Ishikawa, Yuichi,Sakai, Ryuichi
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p. 5789 - 5802,14
(2020/09/15)
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- A facile synthesis of N-substituted maleimides
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A simple and efficient method for the synthesis of N-substituted maleimides from the corresponding maleamic acids under the phase transfer catalysis has been described.
- Deshpande, Sunita R.,Maybhate, Shailaja P.,Likhite, Anjali P.,Chaudhary, Preeti M.
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body text
p. 487 - 488
(2010/10/18)
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- Chemoselective acylation of amines in aqueous media
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Amines are efficiently acylated by both cyclic and acyclic anhydrides by dissolving them in an aqueous medium with the help of a surfactant, sodium dodecyl sulfate (SDS). Cyclic and acyclic anhydrides react with equal ease with an amine, and amines with various stereo-electronic factors react at the same rates with an anhydride. Chemoselective acylation of amines in the presence of phenols and thiols and of thiols in the presence of phenols has been achieved. No acidic or basic reagents are used during the reaction. No Chromatographic separation is required for isolation of the acylated products. Reactions in a neutral aqueous medium, easy isolation of products, and innocuous by-products make the present method a green chemical process. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Naik, Sarala,Bhattacharjya, Gitalee,Talukdar, Bandana,Patel, Bhisma K.
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p. 1254 - 1260
(2007/10/03)
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