- Catalytic System-Controlled Divergent Reaction Strategies for the Construction of Diversified Spiropyrazolone Skeletons from Pyrazolidinones and Diazopyrazolones
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A catalytic system-controlled divergent reaction strategy was here reported to construct four types of intriguing spiroheterocyclic skeletons from simple and readily available starting materials via a precise chemical bond activation/[n+1] annulation cascade. The tetraazaspiroheterocyclic and trizazspiroheterocyclic scaffolds could be independently constructed by a selective N?N bond activation/[n+1] annulation cascade, a C(sp2)-H activation/[4+1] annulation and a novel tandem C(sp2)-H/C(sp3)?H bond activation/[4+1] annulation strategy, along with a broad scope of substrates, moderate to excellent yields and valuable transformations. More importantly, in these transformations, we are the first time to capture a N?N bond activation and a C(sp3)?H bond activation of pyrazolidinones under different catalytic system.
- Fang, Feifei,Hu, Shulei,Li, Chunpu,Wang, Qian,Wang, Run,Han, Xu,Zhou, Yu,Liu, Hong
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- The selective condensation of pyrazolones to isatins in aqueous medium
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The selective condensation of pyrazolones with isatins using water as the reaction medium is presented. This strategy provides an environmentally benign synthetic route to synthesize various potentially bioactive pyrazolone substituted oxindoles.
- Zhang, Yong,Nie, Long-Jun,Luo, Liang,Mao, Jia-Xin,Liu, Jin-Xiang,Xu, Guo-Hai,Chen, Deliang,Luo, Hai-Qing
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- Design, synthesis and biological evaluation of novel pyrazole sulfonamide derivatives as potential AHAS inhibitors
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Acetohydroxy acid synthase (AHAS; EC 2.2.1.6, also referred to as acetolactate synthase, ALS) has been considered as an attractive target for the design of herbicides. In this work, an optimized pyrazole sulfonamide base scaffold was designed and introduced to derive novel potential AHAS inhibitors by introducing a pyrazole ring in flucarbazone. The results of in vivo herbicidal activity evaluation indicates compound 3b has the most potent activity with rape root length inhibition values of 81percent at 100 mg/L, and exhibited the best inhibitory ability against Arabidopsis thaliana AHAS. With molecular docking, compound 3b insert into Arabidopsis thaliana AHAS stably by an H-bond with Arg377 and cation-p interactions with Arg377, Trp574, Tyr579. This study suggests that compound 3b may serve as a potential AHAS inhibitor which can be used as a novel herbicides and provides valuable clues for the further design and optimization of AHAS inhibitors.
- Lv, Xian-Hai,Ren, Zi-Li,Liu, Hao,Li, Hai-Dong,Li, Qing-Shan,Wang, Li,Zhang, Li-Song,Yao, Xiao-Kang,Cao, Hai-Qun
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- Discovery of novel double pyrazole Schiff base derivatives as anti-tobacco mosaic virus (TMV) agents
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Many pyrazole derivatives were reported to exhibit highly activity towards tobacco mosaic virus (TMV). In this work, an optimized pyrazole Schiff base scaffold was designed and introduced to derive novel potential TMV inhibitors. Thirty-six compounds were synthesized, characterized by elemental analysis, mass spectra and nuclear magnetic resonance (NMR) spectroscopy and evaluated by biological experiments. The bioassay results showed that some of the synthesized compounds exhibited excellent anti-TMV activities. Especially, 5-chloro-3-methyl-1H-pyrazole contained compound 4j showed ningnanmycin comparable inhibitory activity and can be considered as potential anti-TMV candidate agent. With molecular docking, compound 4j insert into nucleotide sequence (GAAGUU) of OriRNA stably which revealed nucleotide could be a target of these compounds.
- Lv, Xian-Hai,Ren, Zi-Li,Li, Dong-Dong,Ruan, Ban-Feng,Li, Qing-Shan,Chu, Ming-Jie,Ai, Cheng-Ying,Liu, Dao-Hong,Mo, Kai,Cao, Hai-Qun
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- Preparation and Antibacterial Activity of 3-Methyl-1-p-substituted Phenylpyrazole-5-thiol
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3-Methyl-1-phenylpyrazole-5-thiol (3a) and its p-nitro- (5) and p-fluorophenyl (8) derivatives were prepared as potential antimicrobial agents in relatively good yields. Compounds 3a and 8 showed good antibacterial activities against MRSA, S. aureus, S. epidermidis, E. faecalis, E.faecium, and S. pyogenes. Moreover, compound 3a also showed a synergistic effect with some aminoglycosides.
- Tagawa, Yoshinobu,Minami, Shin'ichi,Yoshida, Toshio,Tanaka, Keitaro,Sato, Shuji,Goto, Yoshinobu,Yamagata, Kenji
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- Discovery of novel triazole-containing pyrazole ester derivatives as potential antibacterial agents
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To develop new antibacterial agents, a series of novel triazole-containing pyrazole ester derivatives were designed and synthesized and their biological activities were evaluated as potential topoisomerase II inhibitors. Compound 4d exhibited the most potent antibacterial activity with Minimum inhibitory concentration (MIC) alues of 4 μg/mL, 2 μg/mL, 4 μg/mL, and 0.5 μg/mL against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella gallinarum, respectively. The in vivo enzyme inhibition assay 4d displayed the most potent topoisomerase II (IC50 = 13.5 μg/mL) and topoisomerase IV (IC50 = 24.2 μg/mL) inhibitory activity. Molecular docking was performed to position compound 4d into the topoisomerase II active site to determine the probable binding conformation. In summary, compound 4d may serve as potential topoisomerase II inhibitor.
- Chu, Ming-Jie,Wang, Wei,Ren, Zi-Li,Liu, Hao,Cheng, Xiang,Mo, Kai,Wang, Li,Tang, Feng,Lv, Xian-Hai
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- Diversity-Oriented Synthesis of Spiropentadiene Pyrazolones and 1 H-Oxepino[2,3- c]pyrazoles from Doubly Conjugated Pyrazolones via Intramolecular Wittig Reaction
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An efficient method for the diversity-oriented synthesis of spiropentadiene pyrazolones and 1H-oxepino[2,3-c]pyrazoles is reported. The methodology attributes O-acylation of phosphorus zwitterions which were formed by a tandem phospha-1,6-addition of PBu3 to α,β,γ,δ-unsaturated pyrazolones, further generating betaine intermediates that preferentially resulted in the aforementioned cyclic products in a diversity-oriented manner. The mechanistic investigations revealed that formation of the betaines is the key step to provide the products via an intramolecular Wittig reaction or an unprecedented δ-C-acylation/cyclization/Wittig reaction.
- Khairnar, Pankaj V.,Wu, Chi-Yi,Lin, Yi-Fang,Edukondalu, Athukuri,Chen, Yi-Ru,Lin, Wenwei
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- Enantioselective Synthesis of Spiropyrazolone-Fused Cyclopenta[ c]chromen-4-ones Bearing Five Contiguous Stereocenters via (3+2) Cycloaddition
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An enantioselective synthesis of spiropyrazolone-fused cyclopenta[c]chromen-4-ones is demonstrated via a (3+2) cycloaddition reaction. The reactions of 3-homoacylcoumarins and α,β-unsaturated pyrazolones in the presence of the cinchona-alkaloid derived hy
- Khairnar, Pankaj V.,Su, Yin-Hsiang,Edukondalu, Athukuri,Lin, Wenwei
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p. 12326 - 12335
(2021/08/24)
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- Rhodium-Catalyzed [4+2] Annulation of N-Aryl Pyrazolones with Diazo Compounds To Access Pyrazolone-Fused Cinnolines
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An efficient synthesis of novel dinitrogen-fused heterocycles such as pyrazolo[1,2-a]cinnoline derivatives have been accomplished by the rhodium(III)-catalyzed reaction of N-arylpyrazol-5-ones with α-diazo compounds. This reaction proceeds through a cascade C?H activation/intramolecular cyclization with a broad substrate scope. Furthermore, this protocol is successfully extended to the unusual phosphorus-containing α-diazo compounds and cyclic diazo compounds as the cross-coupling partners to deliver the two new kinds of pyrazolo[1,2-a]cinnolinones. The control experiments were performed to reveal insight into the mechanism of this reaction, involving reversible C?H activation, migratory insertion of the diazo compound, and cascade cyclization as the key steps of the transformation. Moreover, gram-scale synthesis and further transformation of the target product demonstrate the synthetic utility of the present protocol.
- Dhole, Sandip,Huang, Wan-Wen,Huang, Ying-Ti,Lin, Chih-Yu,Sun, Chung-Ming
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supporting information
p. 4984 - 4992
(2021/09/28)
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- Electrochemical synthesis of versatile ammonium oxides under metal catalyst-, exogenous-oxidant-, and exogenous-electrolyte-free conditions
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An electrochemical oxidative cross-coupling reaction between 2.5-substituted-pyrazolin-5-ones and ammonium thiocyanate has been developed, which resulted in a series of unprecedented cross-coupling products under metal catalyst-, exogenous-oxidant-, and exogenous-electrolyte-free conditions. It is worth noting that since the resulting cross-coupling products are nearly insoluble in MeCN, the pure product could be afforded without silica gel column purification. In addition, the prepared ammonium oxides are versatile building blocks for synthesizing functionalized pyrazole derivatives.
- Yuan, Yong,Li, Liang-Sen,Zhang, Lin,Wang, Feng,Jiang, Lin,Zuo, Lin,Wang, Qi,Hu, Jian-Guo,Lei, Aiwen
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supporting information
p. 2768 - 2771
(2021/03/23)
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- Catalytic Asymmetric Addition of Diorganozinc Reagents to Pyrazole-4,5-Diones and Indoline-2,3-Diones
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The catalytic enantioselective diorganozinc additions to cyclic diketones including pyrazolin-4,5-diones and isatins have been developed. In the presence of morpholine-containing chiral amino alcohol ligand, the corresponding chiral cyclic tertiary alcohols were produced in good to excellent yields (up to 97 %) and enantioselectivities (up to 95 % ee). The notable feature of this protocol includes its mild reaction conditions, Lewis acid additives free and broad functional group tolerance.
- Wang, Rong-Hui,Li, Ya-Ling,He, Hong-Jiao,Xiao, You-Cai,Chen, Fen-Er
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supporting information
p. 4302 - 4306
(2021/02/16)
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- Organophosphane-catalyzed direct β-acylation of 4-arylidene pyrazolones and 5-arylidene thiazolones with acyl chlorides
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An efficient method for the direct β-acylation of arylidene pyrazolones and thiazolones with acyl chlorides in the presence of a base catalyzed by organophosphanes is reported. A variety of functionalized 4-arylidene pyrazolone and 5-arylidene thiazolone derivatives were prepared under metal-free and mild conditions via a tandem phospha-Michael addition/O-acylation/intramolecular cyclization/rearrangement sequence. Our mechanistic investigations revealed that the reaction is highly stereospecific to provide exclusively cis-isomers, and the methodology can also be scaled up with similar efficacy.
- Khairnar, Pankaj V.,Su, Yin-Hsiang,Chen, Yung-Chang,Edukondalu, Athukuri,Chen, Yi-Ru,Lin, Wenwei
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supporting information
p. 6868 - 6872
(2020/09/15)
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- Copper-catalyzed acylation of pyrazolones with aldehydes to afford 4-acylpyrazolones
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Copper-catalyzed direct acylation of the alkenyl C-H bond in 1,2-dihydro-3H-pyrazol-3-ones has been developed, affording a series of 4-acylpyrazolones in moderate to good yields. Notably, this protocol involves readily accessible substrates and reagents, which have good functional group tolerance leading to pyrazolone derivatives under mild reaction conditions.
- Xiao, Yan,Wu, Xiaopeng,Teng, Jiangang,Sun, Song,Yu, Jin-Tao,Cheng, Jiang
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supporting information
p. 7552 - 7557
(2019/08/20)
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- Synthesis of pyrazolones and pyrazoles via Pd-catalyzed aerobic oxidative dehydrogenation
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A palladium-catalyzed oxidative dehydrogenation reaction in the presence of AMS and base to synthesize pyrazolones and pyrazoles was identified. This method can be utilized to a wide range of substrates, operates under mild react conditions and can give high yields. We believe it could be used as an alternative protocol for the classical dehydrogenation reactions.
- Zhu, Ye-Fu,Wei, Bo-Le,Wei, Jiao-Jiao,Wang, Wen-Qiong,Song, Wei-Bin,Xuan, Li-Jiang
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supporting information
p. 1202 - 1205
(2019/03/29)
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- SUBSTITUTED BICYCLIC HETEROCYCLIC COMPOUNDS AS NADPH OXIDASE INHIBITORS
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The present application relates to substituted fused heteroaryl and heterocyclic compounds, useful as nicotinamide adenine dinucleotide phosphate oxidase inhibitors (NADPH oxidase inhibitors), processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by NADPH oxidase. (Formula I)
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Page/Page column 75; 113
(2018/12/03)
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- Pyrazolone and synthetic method of derivative of pyrazolone
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The invention relates to pyrazolone and a synthetic method of a derivative of pyrazolone. The method comprises the steps of preparing acetylacetamide with ketene dimer and ammonium hydroxide being rawmaterials in an ammoniation phase; directly adding substituted hydrazine into an ammoniation kettle to be subjected to a condensation reaction in a condensation phase; adopting concentrated hydrochloric acid to adjust the PH to promote proceeding of a ring-closure reaction in a ring-closure phase; using a cleaning solvent to conduct cleaning to obtain a purified product during aftertreatment. According to the synthetic method, a one-pot method is utilized to synthesize a pyrazolone compound free of solvents, since no solvents exist, the separation and purification process of the product are easily carried out, green production of fine chemicals is effectively achieved, the operation is convenient, the reaction time is obviously shortened, high yield of the product with excellent appearance is achieved, the product yield is increased, the product quality is improved, the yield can reach 88%-98%, and the purity can reach 96%-98%; meanwhile, drainage of wastewater is greatly reduced, andthe problems that the environment pollution is caused, the health of the human kind is harmed, and resources are wasted when water serves as a solvent are fundamentally solved.
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Paragraph 0045; 0046
(2018/03/26)
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- Structure-activity relationships of pyrazole-4-carbodithioates as antibacterials against methicillin–resistant Staphylococcus aureus
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Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious hospital-acquired infections and is responsible for significant morbidity and mortality in residential care facilities. New agents against MRSA are needed to combat rising resistance to current antibiotics. We recently reported 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC) as a new bacteriostatic agent against MRSA that appears to act via a novel mechanism. Here, twenty nine analogs of HMPC were synthesized, their anti-MRSA structure-activity relationships evaluated and selectivity versus human HKC-8 cells determined. Minimum inhibitory concentrations (MIC) ranged from 0.5 to 64 μg/mL and up to 16-fold selectivity was achieved. The 4-carbodithioate function was found to be essential for activity but non-specific reactivity was ruled out as a contributor to antibacterial action. The study supports further work aimed at elucidating the molecular targets of this interesting new class of anti-MRSA agents.
- Majed, Hiwa,Johnston, Tatiana,Kelso, Celine,Monachino, Enrico,Jergic, Slobodan,Dixon, Nicholas E.,Mylonakis, Eleftherios,Kelso, Michael J.
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supporting information
p. 3526 - 3528
(2018/10/15)
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- One-flask synthesis of pyrazolone thioethers involving catalyzed and uncatalyzed thioetherification pathways of pyrazolones
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A one-flask thioetherification of pyrazolones has been demonstrated by transforming several pyrazolones to their corresponding 4-mercaptopyrazolone derivatives and employing them towards cross-coupling with various aromatic and heteroaromatic iodides by applying Pd(OAc)2/xantphos as the catalytic system. The coupling ability of these thiol intermediates with 2,3-dichloropyrazine through an aromatic SN2 pathway has also been established. This methodology provides the use of inexpensive starting materials along with a short reaction time.
- Mukherjee, Prasun,Das, Asish R.
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supporting information
p. 7267 - 7271
(2017/09/25)
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- The discovery of indole derivatives as novel hepatitis C virus inhibitors
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In this study, a library of in-house small molecule was screened using a HCV cell-based assay and a compound (1) containing an N-protected indole scaffold (NINS) was identified as a novel anti-HCV inhibitor. Through structure activity relationship (SAR) study, it was observed that the racemic inhibitor (10m) displayed good anti-HCV activity (EC50 = 1.02 ± 0.10 μM) with the excellent selectivity index (SI = 45.56). Interestingly, R-enantiomer ((R)-10m) showed better anti-HCV activity and lower cytotoxicity than S-enantiomer ((S)-10m). (R)-10m gave the best anti-HCV potency (EC50 = 0.72 ± 0.09 μM) with the highest selectivity index (SI > 69.44). In addition, the mechanism of action study of NINS derivatives demonstrated that NINS derivatives interfere with the early step (viral entry) of the HCV life cycle.
- Han, Zhiqiang,Liang, Xiao,Wang, Yaxin,Qing, Jie,Cao, Lin,Shang, Luqing,Yin, Zheng
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p. 147 - 155
(2016/04/20)
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- POLYCYCLIC DERIVATIVES TARGETING RAL GTPASES AND THEIR THERAPEUTICAL APPLICATIONS
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Contemplated compounds, compositions and methods are directed to Ral GTPase inhibitors with improved activity.
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Paragraph 0172-0173
(2017/01/02)
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- Design, synthesis and anti-tobacco mosaic virus (TMV) activity of 5-chloro-n-(4-cyano-1-aryl-1H-pyrazol-5-yl)-1-aryl-3-methyl-1H-pyrazole-4-carboxamide derivatives
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A series of novel pyrazole amide derivatives 3a-3p which take TMV PC protein as the target has been designed and synthesized by the reactions of 5-chloro-1-aryl-3-methyl-1H-pyrazole-4-carboxylic acids with 5-amino-1-aryl-1H-pyrazole-4-carbonitriles. All the compounds were characterized by 1H-NMR, mass spectroscopy and elemental analysis. Preliminary bioassays indicated that all the compounds acted against the tobacco mosaic virus (TMV) with different in vivo and in vitro modes at 500 μg/mL and were found to possess promising activity. Especially, compound 3p showed the most potent biological activity against tobacco mosaic virus (TMV) compared to ningnanmycin, and a molecular docking study was performed and the binding model revealed that the pyrazole amide moiety was tightly embedded in the binding sites of TMV PC (PDB code: 2OM3).
- Xiao, Jin-Jing,Liao, Min,Chu, Ming-Jie,Ren, Zi-Li,Zhang, Xin,Lv, Xian-Hai,Cao, Hai-Qun
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p. 807 - 821
(2015/01/30)
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- Novel hybrids of 3-n-butylphthalide and edaravone: Design, synthesis and evaluations as potential anti-ischemic stroke agents
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Abstract Fourteen hybrids (10a-g, 11a-g) of 3-n-butylphthalide (NBP) and edaravone (Eda) analogues have been designed and synthesized as potential anti-ischemic stroke agents. In vitro biological studies showed that compounds 10d and 10g exhibited more potent anti-platelet aggregation than ticlopidine (Ticlid), aspirin (ASP) and NBP. Compound 10g more significantly prevented H2O2-mediated neuronal cell (PC12) death than NBP, Eda or NBP together with Eda. Meanwhile, 10g also possessed potent radical scavenging effects on hydroxyl radical (·OH) and superoxide anion radical (·O2-). Our findings may provide new insights into the development of these hybrids, like 10g, for the intervention of ischemic stroke.
- Sheng, Xiao,Hua, Kai,Yang, Chunyu,Wang, Xiaoli,Ji, Hui,Xu, Jinyi,Huang, Zhangjian,Zhang, Yihua
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p. 3535 - 3540
(2015/08/06)
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- Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4- phenoxyquinoline derivatives as potential antitumor agents
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Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50 = 2.20 nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50 values of 0.14 μM, 0.18 μM, 0.09 μM, 0.03 μM, and 1.06 μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.
- Zhou, Shunguang,Ren, Jianguo,Liu, Mingmei,Ren, Lixiang,Liu, Yajing,Gong, Ping
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- Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents
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Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50= 2.20 nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50values of 0.14 μM, 0.18 μM, 0.09 μM, 0.03 μM, and 1.06 μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.
- Zhou, Shunguang,Ren, Jianguo,Liu, Mingmei,Ren, Lixiang,Liu, Yajing,Gong, Ping
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- A facile organocatalyzed Michael addition of pyrazolines to α,β-unsaturated carbonyl compounds
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A new highly efficient cascade reaction of pyrazolines with α,β-unsaturated carbonyl compounds catalyzed by DBU was reported. The process underwent the first deprotection/Michael addition reaction to give 4-substituted pyrazoline derivatives, which were further converted into 4,4-di-substituted pyrazolone derivatives through the second deprotection/Michael reaction. The mechanism for this reaction was also studied.
- Xie, Chen,Lu, Zhijin,Zhou, Wei,Han, Jianlin,Pan, Yi
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supporting information
p. 6650 - 6653
(2013/01/15)
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- New pyrazolones as 11b-HSD1 inhibitors for diabetes
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Compounds of formula as well as pharmaceutically acceptable salts and esters thereof, wherein R1 to R4 have the significance given in claim 1 can be used in the form of pharmaceutical compositions.
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(2010/11/26)
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- Thrombopoietin mimetics
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Invented are non-peptide TPO mimetics. Also invented are novel processes and intermediates used in the preparation of the presently invented compounds. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a selected hydroxy-1-azobenzene derivative.
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- DRUGS COMPRISING COMBINATION OF ANTITHROMBOTIC AGENT WITH PYRAZOLONE DERIVATIVE
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It is intended to provide drugs for treating and/or preventing ischemic diseases which are safe and have little side effects. Namely, drugs comprising a combination of an antithrombotic agent and a pyrazolone derivative defined in the description or its pharmaceutically acceptable salt.
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- Thrombopoietin mimetics
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Non-peptide TPO mimetics are disclosed, as well as a method of treating thrombocytopenia, in a mammal, including a human, in need thereof, which comprises administering to such mammal an effective amount of a selected hydroxy-1-azo-naphthalene derivative.
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(2008/06/13)
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