- Synthesis of novel pyrazole derivatives and their tumor cell growth inhibitory activity
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To find novel antitumor agents, a series of 1H-benzofuro[3,2-c]pyrazole derivatives 4a-e were designed and synthesized. The treatment of 6-methoxybenzofuran-3(2H)-one 3 with LiHMDS in anhydrous tetrahydrofuran (THF) followed by reaction with 3-substitued phenyl isothiocyanate gave the thioamide intermediates, which underwent condensation with hydrazine monohydrate in dioxane/EtOH (1:1) to provide the benzofuropyrazole derivatives 4a–e as well as the unexpected pyrazole derivatives 5a–e. In tumor cell growth inhibitory assay, all the benzofuropyrazole derivatives were not active against the breast tumor MCF-7 cell, only 4a was highly active and more potent than ABT-751 against the leukemia K562 (GI50 = 0.26 μM) and lung tumor A549 cells (GI50 = 0.19 μM), while other benzofuropyrazoles showed very weak inhibitory activity. In contrast, the pyrazoles 5a-e were in general more potent than the benzofuropyrazoles 4a–e. Compound 5a exhibited a similar tendency to that of 4a with high potency against K562 and A549 cells but weak effects on MCF-7 cell. Both pyrazoles 5b and 5e exhibited high inhibitory activities against K562, MCF-7 and A549 cells. The most active compound 5b was much more potent than ABT-751 against K562 and A549 cells with GI50 values of 0.021 and 0.69 M, respectively. Moreover, 5b was identified as a novel tubulin polymerization inhibitor with an IC50 of 7.30 M.
- Cui, Ying-Jie,Tang, Long-Qian,Zhang, Cheng-Mei,Liu, Zhao-Peng
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- Total synthesis of (?)-4-desacetoxy-1-oxovindoline: Single atom exchange of an embedded core heteroatom in vindoline
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A concise total synthesis of (?)-4-desacetoxy-1-oxovindoline is disclosed, bearing a single heteroatom exchange in the core structure of the natural product 4-desacetoxyvindoline. Central to the synthesis is powerful oxadiazole intramolecular [4 + 2]/[3 +
- Boon, Byron A.,Yu, Yi-Yun,Boger, Dale L.
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Read Online
- Discovery of the first-in-class dual PPARδ/γ partial agonist for the treatment of metabolic syndrome
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The peroxisome proliferator-activated receptors (PPARs) exert vital function in the regulation of energy metabolism, which were considered as promising targets of metabolic syndrome. Until now, PPARδ/γ dual agonist is rarely reported, and thereby the pharmacologic action of PPARδ/γ dual agonist is still unclear. In this study, we identified a dual PPARδ/γ partial agonist 6 (ZLY06) based on the cyclization strategy of PPARα/δ dual agonist GFT505. ZLY06 revealed excellent pharmacokinetic profiles suitable for oral medication. Moreover, ZLY06 markedly improved glucolipid metabolism without weight gain, and alleviated fatty liver by promoting the β-oxidation of fatty acid and inhibiting hepatic lipogenesis. In contrast, weight gain and hepatic steatosis were observed in Rosiglitazone, a widely used PPARγ full agonist. All of these results indicated that ZLY06 exhibits potential benefits on metabolic syndrome, while no adverse effects related to PPARγ full agonist.
- Li, Zheng,Ren, Qiang,Zhou, Zongtao,Cai, Zongyu,Wang, Bin,Han, Jing,Zhang, Luyong
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- A Palladium-Catalyzed Oxa-(4+4)-Cycloaddition Strategy towards Oxazocine Scaffolds
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A Pd-catalyzed oxa-(4+4)-cycloaddition between 1-azadienes and (2-hydroxymethyl)allyl carbonates is described. Aurone-derived azadienes furnished polycyclic 1,5-oxazocines in good yields. Interestingly, linear azadienes have also been involved and yielded monocyclic heterocycles with complete regioselectivity. DFT calculations were carried out to gain insight on this observation.
- Scuiller, Ana?s,Liu, Xueyang,Cordier, Marie,Garrec, Julian,Archambeau, Alexis
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p. 981 - 986
(2021/06/02)
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- Aurone derivatives as promising antibacterial agents against resistant Gram-positive pathogens
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A set of variously substituted aurones was synthesized and evaluated against Methicillin-Resistant S. aureus (MRSA) and P. aeruginosa. Several analogues were found active against MRSA, but no effect was recorded against P. aeruginosa. Compounds 27, 30 and 33 showed low cytotoxicity, and were tested against a full range of bacterial (Gram-positive and Gram-negative) and fungal species, including resistant strains. These aurones displayed a selective inhibition of Gram-positive bacteria with excellent Therapeutic Index values, while showing no significant action on several Gram-negative strains, H. pylori and V. alginolyticus being the only susceptible strains among the Gram-negative bacteria tested. A permeabilization assay showed that the antibacterial activity of at least some of the aurones could be linked to alterations of the bacterial membrane. Overall, this study endorses the use of the aurone scaffold for the development of new potent and selective antibacterial agents.
- Olleik, Hamza,Yahiaoui, Samir,Roulier, Brayan,Courvoisier-Dezord, Elise,Perrier, Josette,Pérès, Basile,Hijazi, Akram,Baydoun, Elias,Raymond, Josette,Boumendjel, Ahcène,Maresca, Marc,Haudecoeur, Romain
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p. 133 - 141
(2019/01/23)
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- Design and synthesis of novel senkyunolide analogues as neuroprotective agents
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A class of senkyunolide analogues bearing benzofuranone fragment were designed, synthesized and evaluated for their neuroprotective effect in models of oxygen glucose deprivation (OGD) and oxidative stress. All tested compounds showed neuroprotection profile based on the cell viability assay. In particular, derivatives 1f–1i possessing furoxan-based nitric oxide releasing functionality exhibited significant biological activities in OGD models. More importantly, compound 1g containing short linker with furoxan displayed the most potent neuroprotection at the concentration of 100 μM (cell survival up to 145.2%). Besides, 1g also showed the middle level neuroprotective effect in model of oxidative stress.
- Fang, Yuanying,Wang, Rikang,Wang, Qi,Sun, Yongbing,Xie, Saisai,Yang, Zunhua,Li, Min,Jin, Yi,Yang, Shilin
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p. 668 - 672
(2018/01/27)
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- Benzofuranone derivatives as well as preparation method and application thereof
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The invention discloses benzofuranone derivatives as well as a preparation method and medical application thereof, and provides the benzofuranone derivatives, the preparation method thereof and an application of pharmaceutical composition containing the d
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Paragraph 0018; 0022
(2018/01/11)
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- Synthesis of 6-hydroxyaurone analogues and evaluation of their α-glucosidase inhibitory and glucose consumption-promoting activity: Development of highly active 5,6-disubstituted derivatives
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A series of 6-hydroxyaurones and their analogues have been synthesized and evaluated for their in vitro α-glucosidase inhibitory and glucose consumption-promoting activity. These compounds exhibited varying degrees of α-glucosidase inhibitory activity, 11 of them showing higher potency than that of the control standard acarbose (IC50?=?50.30?μM). Surprisingly, analogues devoid of a substituent at C-2 but having an aryl group at C-5 were found to be highly active (e.g., 7f, IC50?=?9.88?μM). Docking analysis substantiated these findings. The kinetic analysis of compound 7f, the most potent α-glucosidase inhibitor of this study, revealed that it inhibited α-glucosidase in an irreversible and mixed competitive mode. In addition, compounds 7f and 10c exhibited significant glucose consumption promoting activity at 1?μM.
- Sun, Hua,Ding, Weina,Song, Xiaotong,Wang, Dong,Chen, Mingzhu,Wang, Kaili,Zhang, Yazhou,Yuan, Peng,Ma, Ying,Wang, Runling,Dodd, Robert H.,Zhang, Yongmin,Lu, Kui,Yu, Peng
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p. 3226 - 3230
(2017/07/07)
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- Carboxylated aurone derivatives as potent inhibitors of xanthine oxidase
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Xanthine oxidase is a potential target for treatment of hyperuricemia and gout. In this study, a number of A- and B-ring carboxylated aurone derivatives were synthesized and evaluated for their ability to inhibit xanthine oxidase in vitro. According to the results obtained, two different ranges of inhibitory activity were observed. The aurones with carboxylic acid group at the 4′-position of B-ring were found to be potent inhibitors of the enzyme with IC50 values in the low micromolar range. The effects of these compounds were about 50 fold higher than of A-ring modified aurones with carboxymethoxy group at the 6-position. The binding modes of the carboxylated aurones in the active site of xanthine oxidase were explained using molecular docking calculations.
- Muzychka, Oksana V.,Kobzar, Oleksandr L.,Popova, Antonina V.,Frasinyuk, Mykhaylo S.,Vovk, Andriy I.
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p. 3606 - 3613
(2017/06/13)
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- Discovery of benzofuran-3(2H)-one derivatives as novel DRAK2 inhibitors that protect islet β-cells from apoptosis
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Death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is a serine/threonine kinase that plays a key role in a wide variety of cell death signaling pathways. Inhibition of DRAK2 was found to efficiently protect islet β-cells from apoptosis and hence DRAK2 inhibitors represent a promising therapeutic strategy for the treatment of diabetes. Only very few chemical entities targeting DRAK2 are currently known. We carried out a high throughput screening and identified compound 4 as a moderate DRAK2 inhibitor with an IC50value of 3.15?μM. Subsequent SAR studies of hit compound 4 led to the development of novel benzofuran-3(2H)-one series of DRAK2 inhibitors with improved potency and favorable selectivity profiles against 26 selected kinases. Importantly, most potent compounds 40 (IC50?=?0.33?μM) and 41 (IC50?=?0.25?μM) were found to protect islet β-cells from apoptosis in dose-dependent manners. These data support the notion that small molecule inhibitors of DRAK2 represents a promising strategy for the treatment of diabetes.
- Wang, Sheng,Xu, Lei,Lu, Yu-Ting,Liu, Yu-Fei,Han, Bing,Liu, Ting,Tang, Jie,Li, Jia,Wu, Jiangping,Li, Jing-Ya,Yu, Li-Fang,Yang, Fan
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p. 195 - 208
(2017/03/02)
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- Blood-brain barrier permeable anticholinesterase aurones: Synthesis, structure-activity relationship, and drug-like properties
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A series of novel aurones bearing amine and carbamate functionalities at various positions (rings A and/or B) of the scaffold was synthesized and evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activities. Structure-activity relationship study disclosed several potent submicromolar acetylcholinesterase inhibitors (AChEIs) particularly aurones bearing piperidine and pyrrolidine moieties at ring A or ring B. Bulky groups particularly methoxyls, and carbamate to a lesser extent, at either rings were also prominently featured in these AChEI aurones as exemplified by the trimethoxyaurone 4-3. The active aurones exhibited a lower butyrylcholinesterase inhibition. A 3g€2-chloroaurone 6-3 originally designed to improve the metabolic stability of the scaffold was the most potent of the series. Molecular docking simulations showed these AChEI aurones to adopt favourable binding modes within the active site gorge of the Torpedo californica AChE (TcAChE) including an unusual chlorine-π interaction by the chlorine of 6-3 to establish additional bondings to hydrophobic residues of TcAChE. Evaluation of the potent aurones for their blood-brain barrier (BBB) permeability and metabolic stability using PAMPA-BBB assay and in vitro rat liver microsomes (RLM) identified 4-3 as an aurone with an optimal combination of high passive BBB permeability and moderate CYP450 metabolic stability. LC-MS identification of a mono-hydroxylated metabolite found in the RLM incubation of 4-3 provided an impetus for further improvement of the compound. Thus, 4-3, discovered within this present series is a promising, drug-like lead for the development of the aurones as potential multipotent agents for Alzheimer's disease.
- Liew, Kok-Fui,Chan, Kit-Lam,Lee, Chong-Yew
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p. 195 - 210
(2015/03/18)
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- Practical, modular, and general synthesis of 3-coumaranones through gold-catalyzed intermolecular alkyne oxidation strategy
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A gold-catalyzed intermolecular alkyne oxidation for the preparation of 3-coumaranones has been developed. Using 8-isopropylquinoline N-oxides as oxidants, the reactions of o-ethynylanisoles afford versatile 3-coumaranones in moderate to good isolated yields. The synthetic utility of this chemistry is also indicated by the synthesis of the natural product sulfuretin.
- Shu, Chao,Liu, Rongfu,Liu, Shuang,Li, Jian-Qiao,Yu, Yong-Fei,He, Qiao,Lu, Xin,Ye, Long-Wu
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supporting information
p. 91 - 95
(2015/02/19)
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- Synthesis of aurones and their inhibitory effects on nitric oxide and PGE2 productions in LPS-induced RAW 264.7 cells
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Sulfuretin is one of major constituents of Rhus verniciflua that exerts anti-inflammatory activities. Some of aurones were synthesized as sulfuretin derivatives and evaluated for their abilities to inhibit NO and PGE2 production in LPS-induced RAW 264.7 cells in order to reveal the relationship. Of the aurones synthesized in the present study, 2h and 2i, which possess C-6 hydroxyl group in A-ring and methoxy substituents in B-ring, more potently inhibited NO and PGE2 production and were less cytotoxic than sulfuretin.
- Shin, Seo Young,Shin, Min Cheol,Shin, Ji-Sun,Lee, Kyung-Tae,Lee, Yong Sup
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scheme or table
p. 4520 - 4523
(2011/09/12)
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- Novel benzofuran derivatives with dual 5-HT1A receptor and serotonin transporter affinity
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Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT1A receptor affinities. Their design, synthesis and structure-activity relationships are described.
- Venkatesan, Aranapakam M.,Dos Santos,Ellingboe, John,Evrard, Deborah A.,Harrison, Boyd L.,Smith, Deborah L.,Scerni, Rosemary,Hornby, Geoffrey A.,Schechter, Lee E.,Andree, Terrence H.
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scheme or table
p. 824 - 827
(2010/06/13)
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- Design, synthesis and anticholinesterase activity of a novel series of 1-benzyl-4-((6-alkoxy-3-oxobenzofuran-2(3H)-ylidene) methyl) pyridinium derivatives
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A novel series of benzofuranone-ylidene-methyl benzylpyridinium derivatives (6a-u) were synthesized as acetylcholinesterase inhibitors. The anticholinesterase activity of synthesized compounds was measured using colorimetric Ellman's method. It was revealed that some synthesized compounds exhibited high anticholinesterase activity, among them compound 6b was the most active compound (IC50 = 10 ± 6.87 nM).
- Nadri, Hamid,Pirali-Hamedani, Morteza,Shekarchi, Maryam,Abdollahi, Mohammad,Sheibani, Vahid,Amanlou, Massoud,Shafiee, Abbas,Foroumadi, Alireza
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experimental part
p. 6360 - 6366
(2010/10/01)
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- Regioselective synthesis of tetrasubstituted pyrroles by 1,3-dipolar cycloaddition and spontaneous decarboxylation
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We developed a novel regioselective synthesis of tetrasubstituted pyrroles via the classic 1,3-dipolar cycloaddition of α,β-unsaturated benzofuran-3(2H)-one and azlactones (1) followed by spontaneous decarboxylation. The complete regiochemical control of tetrasubstituted pyrroles was confirmed by the orthogonal synthesis of complementary regioisomers (7a and 7b) simply by using different azlactones (1a and 1b, respectively).
- Kim, Yongju,Kim, Jonghoon,Park, Seung Bum
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supporting information; experimental part
p. 17 - 20
(2009/08/07)
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- BENZOFURANYL- AND BENZOTHIENYL- PIPERAZINYL QUINOLINES AND METHODS OF THEIR USE
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Benzofuranyl- and benzothienyl-piperzinyl quinoline derivatives and compositions containing such compounds are disclosed. Methods of using benzofuranyl- and benzothienyl-piperzinyl quinoline derivatives and compositions containing such composition in the treatment and/or prevention of serotonin-related disorders, such as depression and anxiety, are also disclosed. In addition, processes for the preparation of benzofuranyl- and benzothienyl-piperzinyl quinoline derivatives are disclosed.
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(2009/04/24)
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- New scaffolds for the design of selective estrogen receptor modulators
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In the present work we report the synthesis of four new ER ligands which can be used as scaffolds for the introduction of the basic side chains necessary for antiestrogenic activity. Affinities and agonist/antagonist characterization of the ligands for both ERα and ERβ have been determined in a competitive radioligand assay, and in an in vitro coactivator recruitment functional assay, respectively. Molecular modelling techniques have been used in order to rationalize the experimental results. Compound 2 is reported as a novel ERβ-agonist/ERα-antagonist. Two compounds show an interesting antitumour profile towards two pancreatic cancer cell lines and have been selected for in vivo assays.
- Martin-Santamaria, Sonsoles,Rodriguez, Jose-Juan,De Pascual-Teresa, Sonia,Gordon, Sandra,Bengtsson, Martin,Garrido-Laguna, Ignacio,Rubio-Viqueira, Belen,Lopez-Casas, Pedro P.,Hidalgo, Manuel,De Pascual-Teresa, Beatriz,Ramos, Ana
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experimental part
p. 3486 - 3496
(2009/02/05)
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- Asymmetric synthesis of N-substituted N-hydroxyureas
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Asymmetric synthesis of (S)-N-(1-arylethyl)-N-hydroxyureas, (S)-N-(6-methoxy)- and (S)-N-(6-benzyloxy-2,3-dihydrobenzofuran-3-yl)-N-hydroxyurea- lipoxygenase inhibitor, is described. Three approaches to the formation of the N-hydroxyurea moiety at the stereogenic center have been used. The first one, via the reaction of (R)-6-benzyloxy-2,3-dihydrobenzofuran-3-ol with N,O-bis(phenoxycarbonyl)hydroxylamine under Mitsunobu conditions, leads to a partially racemized product. Alternatively, the enantioselective reduction of oximes O-benzyl ethers of acetophenone, 4-methoxy- and 4-benzyloxyacetophenone, 6-methoxy- and 6-benzyloxy-2,3-dihydrobenzofuran-3-one with borane/oxazaborolidines can be controlled to produce either the corresponding hydroxylamine O-benzyl ethers or primary amines which have been transformed into N-substituted N-hydroxyureas in 57% to 99% ee.
- Laczkowski, Krzysztof Z.,Pakulski, Marcin M.,Krzeminski, Marek P.,Jaisankar, Parasuraman,Zaidlewicz, Marek
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p. 788 - 795
(2008/09/20)
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- Synthesis, antibacterial activity, and quantitative structure-activity relationships of new (Z)-2-(nitroimidazolylmethylene)-3(2 H)-benzofuranone derivatives
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A new series of (Z)-2-(1-methyl-5-nitroimidazole-2-ylmethylene)-3(2 H)-benzofuranones (11a-p) and (Z)-2-(1-methyl-4-nitroimidazole-5-ylmethylene)-3(2 H)-benzofuranones (12a-m) were synthesized and assayed for their antibacterial activity against Gram-positive and Gram-negative bacteria. Most of the 5-nitroimidazole analogues (11a-p) showed a remarkable inhibition of a wide spectrum of Gram-positive bacteria (Staphylococcus aureus, Streptococcus epidermidis, MRSA, and Bacillus subtilis) and Gram-negative Klebsiella pneumoniae, whereas 4-nitroimidazole analogues (12a-m) were not effective against selected bacteria. The quantitative structure-activity relationship investigations were applied to find out the correlation between the experimentally evaluated activities with various parameters of the compounds studied. The QSAR models built in this work had reasonable predictive power and could be explained by the observed trends in activities.
- Hadj-esfandiari, Narges,Navidpour, Latifeh,Shadnia, Hooman,Amini, Mohsen,Samadi, Nasrin,Faramarzi, Mohammad Ali,Shafiee, Abbas
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p. 6354 - 6363
(2008/09/21)
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- COMPOUNDS AND METHODS OF USE
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Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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Page/Page column 86-87
(2008/06/13)
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- Piperidinyl indole and tetrohydropyridinyl indole derivatives and method of their use
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3-Piperidin-4-yl-1H-indole and 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives are disclosed. Methods of using the derivatives and compositions containing the derivatives in the prevention and/or treatment of serotonin disorders, such as depression and anxiety, are also disclosed. Additionally, processes for the preparation of 3-piperidin-4-yl-1H-indole and 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives are disclosed.
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Page/Page column 13
(2010/02/10)
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- BENZOFURANYL-AND BENZOTHIENYL-PIPERAZINYL QUINOLINES AND METHODS OF THEIR USE
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Benzofuranyl-and benzothienyl-piperzinyl quinoline derivatives and compositions containing such compounds are disclosed. Methods of using benzofuranyl- and benzothienyl-piperzinyl quinoline derivatives and compositions containing such composition in the treatment and/or prevention of serotonin-related disorders, such as depression and anxiety, are also disclosed. In addition, processes for the preparation of benzofuranyl- and benzothienyl-piperzinyl quinoline derivatives are disclosed.
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- Substituted aurone derivatives
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A method for treating a fungal infection is disclosed. The method includes administering to a patient a pharmaceutical composition containing a compound of formula (IA): where each R is independently H, OH, Br, Cl, I, amino, thiol, nitro, C1-4a
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- Action of Benzoyl Peroxide on 6-Methoxy- and 6-Hydroxy-coumaran-3-ones and the Reaction of Paraldehyde with 6-Methoxycoumaran-3-one
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Benzoyl peroxide reacts with 6-methoxycoumaran-3-one (I, R=CH3) to give 2-benzoyloxy derivative (II, R=CH3).To establish its structure, 2-hydroxy-6-methoxycoumaran-3-one (IV) has been synthesised by oxidising 2-hydroxy-4-methoxyacetophenone with SeO2 in dioxane.Benzoylation of IV gives II (R = CH3). 6-Hydroxycoumaran-3-one (I, R = H) also reacts with (BzO)2 to give 2-benzoyloxy derivative (II, R = H).The (BzO)2 reactions with both the coumaranones (I, R = CH3 and H) suggest greater nucleophility at C-2 than at C-5 or C-6.Similar reactivity at C-2 is also evident from the condensation of I (R = CH3) with paraldehyde in dioxane-K2CO3, giving ethylidene-2,2'-bis-6-methoxycoumaran-3-one.
- Aslam Ansari, M.,Mathur, K. B. L.,Ahluwalia, V. K.
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p. 104 - 106
(2007/10/02)
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