- Synthesis and evaluation of new phenyl acrylamide derivatives as potent non-nucleoside anti-HBV agents
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As a continuation of our previous work, a series of new phenyl acrylamide derivatives (4Aa-g, 4Ba-t, 5 and 6a-c) were designed and synthesized as non-nucleoside anti-HBV agents. Among them, compound 4Bs could potently inhibit HBV DNA replication in wild-type and lamivudine (3TC)/entecavir resistant HBV mutant strains with IC50 values of 0.19 and 0.18 μM, respectively. Notably, the selective index value of 4Bs was above 526, indicating the favorable safety profile. Interestingly, unlike nucleoside analogue 3TC, 4Bs could significantly inhibit 3.5 kb pgRNA expression. Molecular docking study revealed that 4Bs could fit well into the dimer-dimer interface of HBV core protein by hydrophobic, π–π and H-bond interactions. Considering the potent anti-HBV activity, low toxicity and diverse anti-HBV mechanism from that of nucleoside anti-HBV agent 3TC, compound 4Bs might be a promising lead to develop novel non-nucleoside anti-HBV therapeutic agents, and warranted further investigation.
- Gu, Xiaoke,Zhang, Yinpeng,Zou, Yueting,Li, Xin,Guan, Mingyu,Zhou, Qingqing,Qiu, Jingying
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- Nickel-Catalyzed Asymmetric Hydrogenation of 2-Amidoacrylates
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Earth-abundant nickel, coordinated with a suitable chiral bisphosphine ligand, was found to be an efficient catalyst for the asymmetric hydrogenation of 2-amidoacrylates, affording the chiral α-amino acid esters in quantitative yields and excellent enantioselectivity (up to 96 % ee). The active catalyst component was studied by NMR and HRMS, which helped us to realize high catalytic efficiency on a gram scale with a low catalyst loading (S/C=2000). The hydrogenated products could be simply converted into chiral α-amino acids, β-amino alcohols, and their bioactive derivatives. Furthermore, the catalytic mechanism was investigated using deuterium-labeling experiments and computational calculations.
- Chen, Jianzhong,Gridnev, Ilya D.,Hu, Yawen,Li, Bowen,Zhang, Wanbin,Zhang, Zhenfeng
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supporting information
p. 5371 - 5375
(2020/02/15)
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- Design, synthesis, and biological evaluation of novel 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives as cytotoxic agents and COX-2/LOX inhibitors
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A new series of 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives 4a–l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, 1H NMR, DEPT-Q NMR, and mass spectroscopy) and elemental analyse
- Lamie, Phoebe F.,Philoppes, John N.,Rárová, Lucie
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- Synthesis and biological testing of (5Z)-2-aryl-5-arylmethylidene-3,5-dihydro-4H-imidazol-4-ones as antimitotic agents
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Compounds interacting with cell protein tubulin and microtubules represent an important type of antimitotic agents. A series of tubulin-targeted 2-aryl-4-benzoyl-imidazoles were reported to possess high cytotoxicity, and so, we prepared a series of structural isomers of these to be evaluated as antimitotic agents. The synthesis of the novel (Z)-2-aryl-5-arylmethylidene-3,5-dihydro-4H-imidazol-4-ones involved coupling of substituted hippuric acids with aromatic aldehydes. Subsequent conversion of the resulting oxazolones to the corresponding imidazolones was carried out under microwave irradiation in the presence of urea and ammonium acetate. The cytotoxicity of the majority of the compounds to human epithelial carcinoma cancer cell line A549 was in the sub-micromolar range and was found to be more sensitive to the substituents on the 5-arylmethylidene fragment than on the 2-aryl ring in general. The cytotoxicities of the synthesized compounds were lower than those of the previously reported isomeric 2-aryl-4-benzoyl-imidazoles, and the basic structure–activity relationships in the isomeric pairs were different. Synthesized (5Z)-5-[(4-bromophenyl)methylidene]-2-(4-methylphenyl)-3,5-dihydro-4H-imidazol-4-one, which had the highest cytotoxicity (IC50?~?440?nM) in the series of novel compounds, had a definite cytostatic effect on the A549 cells, but its antiproliferative properties were not linked to action on the microtubules. This would be an interesting lead compound for additional investigation into the mechanism of cytostatic action, and further structural optimization.
- Beloglazkina, Anastasia A.,Wobith, Birgit,Barskaia, Elena S.,Zefirov, Nikolay A.,Majouga, Alexander G.,Beloglazkina, Elena K.,Zyk, Nikolay V.,Kuznetsov, Sergei A.,Zefirova, Olga N.
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p. 1239 - 1249
(2016/07/06)
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- Synthesis and Quantitative Structure-activity Relationships Study for Arylpropenamide Derivatives as Inhibitors of Hepatitis B Virus Replication
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A series of new arylpropenamide derivatives containing different aryl groups were synthesized, characterized, and evaluated for their anti-hepatitis B virus (HBV) activities. A new high accuracy QSAR model of arylpropenamide was constructed based on a more completely activities data and calculation parameter. The 2D-QSAR equations, by using DFT and multiple linear regression analysis methods, revealed that higher value of thermal energy (TE) and lower entropy (S?) increase the anti-HBV activities of the arylpropenamide molecules. Predictive 3D-QSAR models were established by SYBYL multifit molecular alignment rule. The optimum models were all statistically significant with cross-validated and conventional coefficients, indicating that they were reliable enough for activity prediction.
- Min, Ma,Xingjun, Jiang,Xueding, Wang,Hao, Zou,Weiqing, Yang,Yuanyuan, Zhang,Changrong, Peng,Zicheng, Li,Jing, Yang,Quan, Du,Menglin, Ma
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p. 451 - 459
(2016/10/19)
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- Catalytic aza-wittig reaction of acid anhydride for the synthesis of 4H-benzo[d][1,3]oxazin-4-ones and 4-benzylidene-2-aryloxazol-5(4H)-ones
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Compared to the aza-Wittig reaction of aldehydes, ketones, amides, and esters, the aza-Wittig reaction of acid anhydride was always overlooked, which should be an important part of Wittig reactions. Here, the aza-Wittig reaction of anhydride and catalytic aza-Wittig reaction of anhydride were both developed with high yields, which provides an efficient method to synthesize of 4H-benzo[d][1,3]oxazin-4-ones and 4-benzylidene-2-aryloxazol-5(4H)-ones. The strategy of copper-catalyzed reduction of phosphine oxide was used and found effective for this transformation. Additionally, the one-pot catalytic aza-Wittig reaction of carboxylic acids was achieved. Furthermore, NMR experiments and Hammett plot recorded the process of catalytic aza-Wittig reaction of anhydride, which provides direct proof that the copper-catalyzed reduction of waste phosphine oxide is the key step in this transformation.
- Wang, Long,Xie, Yi-Bi,Huang, Nian-Yu,Yan, Jia-Ying,Hu, Wei-Min,Liu, Ming-Guo,Ding, Ming-Wu
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p. 4010 - 4016
(2016/07/06)
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- 5(4H)-Oxazolones as Novel Antitubercular Agents: Synthesis, Characterisation and Structure Activity Study
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In search of novel anti tubercular agents, a series of twelve 4-(substituted benzylidene)-2-p-tolyloxazol-5(4H)-ones (5a-5l) has been synthesized, characterised and subjected to evaluate their antitubercular activity for the first time against Mycobacterium tuberculosis H37Rv (ATCC 27294). The out-put of these studies disclosed that all the synthesized target molecules of the series displayed good to moderate activity with MIC values ranging 2-32 μg/mL in comparison with the standard first line antitubercular drugs Rifampicin and Isoniazid. Compound 5e with three methoxy groups meta to each other, is the most distinctive compound identified amongst the series, because of its remarkable in vitro antitubercular activity and thus may act as a promising lead molecule for further explorations.
- Suhasini,Chintakindi, Praveen K.,Chaguruswamy,Murthy
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p. 855 - 860
(2015/10/29)
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- Phenylpropenamide derivatives: Anti-hepatitis B virus activity of the Z isomer, SAR and the search for novel analogs
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Phenylpropenamides have been reported to be a class of non-nucleoside inhibitors of the hepatitis B virus (HBV). This class of compounds was explored with the objective of developing potent anti-HBV agents, with a novel mechanism of action, that could be combined with nucleos(t)ide analogs currently used to treat HBV infection. To accomplish this objective a series of substituted arylpropenamide derivatives were prepared and the E and Z geometrical isomers were separated. The structural identity of each of the E and Z isomers was determined by single crystal X-ray crystallography. Contrary to previous reports, the activity of this class of molecules resides in the Z isomer. Further structure-activity relationship studies around the active Z isomer identified compounds that displayed potent antiviral activity against HBV with EC90 value of approximately 0.5 μM in vitro. Attempts to develop ring constrained analogs did not lead to active HBV inhibitors.
- Wang, Peiyuan,Naduthambi, Devan,Mosley, Ralph T.,Niu, Congrong,Furman, Phillip A.,Otto, Michael J.,Sofia, Michael J.
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p. 4642 - 4647
(2011/09/12)
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- Phenylpropenamide derivatives as inhibitors of hepatitis B virus replication
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A non-nucleoside class of compounds that inhibits the replication of hepatitis B virus (HBV) in cell culture has been discovered. A series of substituted analogues of phenylpropenamide 6 has been prepared and evaluated in the HepAD38 cellular assay. Structure-activity relationships of this series are discussed. (C) 2000 Elsevier Science Ltd.
- Perni, Robert B.,Conway, Samuel C.,Ladner, Stephanie K.,Zaifert, Katie,Otto, Michael J.,King, Robert W.
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p. 2687 - 2690
(2007/10/03)
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- Synthesis of Isomeric Methyl- and Dimethyl-Substituted 4-Benzylidene-2-phenyloxazolin-5-ones and Ring-Opened Derivatives
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4-Benzylidene-2-phenyloxazolin-5-one and 15 mono- and dimethylated isomers as well as their ring-opened methyl ester and acid derivatives have been synthesized.Absorption spectroscopy indicates insignificant changes in the chromophore due to the methyl groups.
- Nicholas, Everton S.,Phelps, David J.
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