- Synthesis of pyrazine-2,3-dicarbonitriles via the one-pot three-component reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione, diaminomaleonitrile, and functionalized alcohols in acetonitrile
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An efficient one-pot three-component reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione, diaminomaleonitrile, and alcohols with hetero-atom substituents or several hydroxyl groups in acetonitrile solvent under reflux led to the formation o
- Shahnaei, Roya,Kabirifard, Hassan,Fathololoomi, Parinaz
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Read Online
- A simple and versatile protocol for the preparation of functionalized heterocycles utilizing 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione
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The reaction of ethyl benzoylpyruvate with phenyl isothiocyanate in alkaline medium yields 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1). Reaction of the intermediate 1 with primary aromatic amines such as aniline derivatives, benzidine and s
- Kabirifard, Hassan,Ghahremani, Samira,Afsharpoor, Anita
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- Reactions of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione and diaminomaleonitrile in the presence of alcohols as reactant and solvent
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The one-pot synthesis of a novel class of 5-(2-alkoxy-2-phenyl-1-N-phenylthiocarbamoylethenyl)-6-oxo-1,6-dihydropyrazine-2,3-dicarbonitriles (2a–o) is achieved in moderate to good yields by the sequential reaction between 4-benzoyl-5-phenylamino-2,3-dihyd
- Moloudi, Maryam,Kabirifard, Hassan,Kabirifard, Raihaneh,Mahdikhani, Mona
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- Synthesis of Organic Ligands via Reactions of 4-Benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione with N -Nucleophiles
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The reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) with aminoheteroaryls, lamotrigine, 1,3-diaminoheteroaryls, dapsone, NH2R (hydroxylamine, DL-1-phenylethylamine, and metformin), and 4,4′-bipyridine in THF/H2O (1: 1) at room tempe
- Bagherinejad, Hanieh,Golabian, Elaheh,Hafez Taghva, Pardis,Hossein Roodbari, Maryam,Javadpour, Parastoo,Kabirifard, Hassan,Koosheshi, Niloofar,Seyfi, Soheila,Teimouri, Hossein
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Read Online
- Small-molecule vasopressin-2 receptor antagonist identified by a G-protein coupled receptor "pathway" screen
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G-protein-coupled receptors (GPCRs) such as the vasopressin-2 receptor (V2R) are an important class of drug targets. We developed an efficient screen for GPCR-induced cAMP elevation using as read-out cAMP activation of cystic fibrosis transmemb
- Yangthara, Buranee,Mills, Aaron,Chatsudthipong, Varanuj,Tradtrantip, Lukmanee,Verkman, Alan S.
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- Novel Substituted Purine Isosteres: Synthesis, Structure-Activity Relationships and Cytotoxic Activity Evaluation
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A number of pyrrolo[2,3-c]pyridines, pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines were designed and synthesized as antiproliferative agents. The target compounds possessed selected substituents in analogous positions on the central scaffold th
- Dimitrakis, Spyridon,Gavriil, Efthymios-Spyridon,Gioti, Katerina,Lougiakis, Nikolaos,Marakos, Panagiotis,Pouli, Nicole,Pousias, Athanasios,Tenta, Roxane
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- Design, synthesis, and biological activity evaluation of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives as broad-spectrum antifungal agents
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To discover antifungal compounds with broad-spectrum and stable metabolism, a series of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives was designed and synthesized. Compounds A30-A34 exhibited excellent broad-spectrum antifungal activity against Candida albicans with MIC values in the range of 0.03–0.5 μg/mL, and against Cryptococcus neoformans and Aspergillus fumigatus with MIC values in the range of 0.25–2 μg/mL. In addition, compounds A31 and A33 showed high metabolic stability in human liver microsomes in vitro, with the half-life of 80.5 min and 69.4 min, respectively. Moreover, compounds A31 and A33 showed weak or almost no inhibitory effect on the CYP3A4 and CYP2D6. The pharmacokinetic evaluation in SD rats showed that compound A31 had suitable pharmacokinetic properties and was worthy of further study.
- Zhao, Liyu,Sun, Yin,Yin, Wenbo,Tian, Linfeng,Sun, Nannan,Zheng, Yang,Zhang, Chu,Zhao, Shizhen,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
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- Synthesis and Biological Screening of Novel 5-(5-Aryl-1-phenyl-1H-pyrazol-3-yl)-3-aryl-1,2,4-oxadiazole Derivatives
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A new series of 5-(5-aryl-1-phenyl-1H-pyrazol-3-yl)-3-aryl-1,2,4-oxadiazole (6a-o) have been synthesized by a cyclocondensation reaction of ethyl 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (3a-c) with aryl imidoxime (5a-e). The newly synthesize
- Agrawal, Brijmohan R.,Farooqui, Mazahar,Khandebharad, Amol U.,Kulkarni, Pravin S.,Sarda, Swapnil R.
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p. 209 - 215
(2022/01/06)
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- RETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance
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Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negati
- Singh, Kumar Sachin,Sharma, Rishabh,Reddy, Poli Adi Narayana,Vonteddu, Prashanthi,Good, Madeline,Sundarrajan, Anjana,Choi, Hyeree,Muthumani, Kar,Kossenkov, Andrew,Goldman, Aaron R.,Tang, Hsin-Yao,Totrov, Maxim,Cassel, Joel,Murphy, Maureen E.,Somasundaram, Rajasekharan,Herlyn, Meenhard,Salvino, Joseph M.,Dotiwala, Farokh
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p. 597 - 602
(2020/12/25)
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- ISPH INHIBITORS, AND METHODS OF MAKING AND USING SAME
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In one aspect, the invention provides novel compounds useful for treating bacterial infections, such as but not limited to Gram-negative bacterial infections. In another aspect, the invention provides novel compounds useful for activating γδ T cell respon
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Page/Page column 30; 34-35
(2021/02/05)
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- Lewis acid-promoted synthesis of highly substituted pyrrole-fused benzoxazinones and quinoxalinones
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A synthesis of a series of novel fused tricyclic heterocyclic compounds has been achieved in one-pot reaction set up starting from (E)-3-(2-oxo-2-phenylethylidene)indolin-2-one and 1,4-benzoxazinone/quinoxalinone derivatives promoted by tin(IV) chloride.
- Selvendran, Suresh,Rajendran, Saravanakumar
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supporting information
p. 437 - 445
(2020/10/22)
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- Novel N-benzylpiperidine derivatives of 5-arylisoxazole-3-carboxamides as anti-Alzheimer's agents
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The complex pathophysiology of Alzheimer's disease (AD) has prompted researchers to develop multitarget-directed molecules to find an effective therapy against the disease. In this context, a novel series of N-(1-benzylpiperidin-4-yl)-5-arylisoxazole-3-ca
- Saeedi, Mina,Felegari, Peyman,Iraji, Aida,Hariri, Roshanak,Rastegari, Arezoo,Mirfazli, S. Sara,Edraki, Najmeh,Firuzi, Omidreza,Mahdavi, Mohammad,Akbarzadeh, Tahmineh
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- A new synthetic approach for pyrazolo[1,5-a]pyrazine-4(5H)-one derivatives and their antiproliferative effects on lung adenocarcinoma cell line
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Abstract: Starting from the 3,5-dimethyl pyrazole ring and acetophenone derivatives, five different N-propargylated C-3 substituted pyrazoles were obtained. These derivatives were reacted with different amine derivatives using Cs2CO3 in methanol and 11 different pyrazolo [1,5-a] pyrazine-4(5H)-one derivatives were obtained, which are not found in the literature. The cytotoxic effects of these derivatives in the A549 cell line were investigated. The 160?μM concentration of two derivatives was found to increase cell death rate to 50%, and two derivatives increased cell death rate by up to 40%. The structure–activity relationship (SAR) study revealed an amide group with a long alkyl chain and benzene ring with a p-CF3 group could be important for efficiency. With theoretical ADMET studies of pyrazolopyrazine derivatives, pharmacokinetic phases were predicted to be suitable. Graphic abstract: [Figure not available: see fulltext.].
- Uygun, Meltem Tan,Amudi, Karina,Tura?l?, ?rem Do?an,Menges, Nurettin
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- Synthesis, in vitro anticancer activity and in silico studies of certain isoxazole-based carboxamides, ureates, and hydrazones as potential inhibitors of VEGFR2
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The ensuing research presents the results of in vitro anticancer activity of novel 28 compounds of isoxazole–based carboxamides 3(a-d); ureates 4(a-g), 5, 6, 7a,b, 8; and hydrazones 9(a-f), 10(a-d), 11a,b as potential inhibitors of VEGFR2. The carboxamide
- Abou-Seri, Sahar M.,Behery, Mohamed G. M.,Eissa, Amal A. M.,Omar, Farghaly A.
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- Green synthesis method of nicotinic acid ester compounds based on non-metallic conditions
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The invention discloses a green synthesis method based on nicotinic acid ester compounds under non-metallic conditions, and belongs to the technical field of organic synthesis. The method comprises the following steps of (III) replacing cyclopropanol and (II) substituted enamine ester as a raw material, taking tetramethyl piperidine nitrogen oxide as an oxidizing agent, 110 - 130 °C, stirring and reacting in an organic solvent to synthesize a (I) nicotinate compound. The invention provides a green synthesis method based on nicotinic acid ester compounds under non-metallic conditions, wherein cyclopropanols and enamine esters are taken as raw materials, and a polysubstituted nicotinate is synthesized through a strategy of oxidative dehydrogenation of ketene cyclization.
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Paragraph 0052-0054
(2021/09/29)
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- Design and synthesis of novel 5-arylisoxazole-1,3,4-thiadiazole hybrids as α-glucosidase inhibitors
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Background: α-Glucosidase inhibitors have occupied a significant position in the treatment of type 2 diabetes. In this respect, the development of novel and efficient non-sugar-based inhibitors is in high demand. Objective: Design and synthesis of new 5-arylisoxazole-1,3,4-thiadiazole hybrids possessing α-glucosidase inhibitory activity were developed. Methods: Different derivatives were synthesized by the reaction of various 5-arylisoxazole-3-carboxylic acids and ethyl 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)acetate. Finally, they were evalu-ated for their α-glucosidase inhibitory activity. Results: It was found that ethyl 2-((5-(5-(2-chlorophenyl)isoxazole-3-carboxamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5j) was the most potent compound (IC50 = 180.1 μM) compared with acarbose as the reference drug (IC50 = 750.0 μM). Also, the kinetic study of 5j revealed a competitive inhibition and docking study results indicated desired interactions of that compound with amino acid residues located close to the active site of α-glucosidase. Conclusion: Good α-glucosidase inhibitory activity obtained by the title compounds introduced them as an efficient scaffold, which merits to be considered in anti-diabetic drug discovery developments.
- Akbarzadeh, Tahmineh,Eslami, Azadeh,Faramarzi, Mohammad Ali,Mahdavi, Mohammad,Mirfazli, Seyedeh Sara,Saeedi, Mina,Zardkanlou, Mahsa
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p. 436 - 444
(2021/10/04)
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- Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of β-Substituted α-Oxobutyrolactones
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A concise and effective ruthenium-catalyzed asymmetric transfer hydrogenation of β-substituted α-oxobutyrolactones has been developed, delivering a series of cis-β-substituted α-hydroxybutyrolactone derivatives with excellent yields, enantioselectivities,
- Hu, Zi-Qi,Li, Xiang,Liu, Li-Xia,Yu, Chang-Bin,Zhou, Yong-Gui
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supporting information
p. 17453 - 17461
(2021/11/18)
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- Ring-chain transformation of 4-aroyl-5-phenylamino-2,3-dihydrothiophene-2,3-diones: Facile and efficient synthesis of novel pyrrolo[2,3-c]pyrazol-3(2H)-ones and 1,2-dihydro-5H,6H-pyridazine-5,6-diones
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Seven, novel pyrrolo[2,3-c]pyrazol-3(2H)-one and 1,2-dihydro-5H,6H-pyridazine-5,6-dione chromophores were synthesized by the reaction of 4-aroyl-5-phenylamino-2,3-dihydrothiophene-2,3-diones with cyanoacetohydrazide and arylhydrazines such as phenylhydrazine and 4-nitrophenylhydrazine. These derivatives were characterized by elemental analysis, IR, UV-Visible, 1H, 13C NMR and mass spectroscopy. Spectral characteristics of the compounds were studied in four organic solvents of differing polarity.
- Hafez Taghva, Pardis,Kabirifard, Hassan
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p. 200 - 209
(2019/12/30)
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- Design and Synthesis of Novel Arylisoxazole-Chromenone Carboxamides: Investigation of Biological Activities Associated with Alzheimer's Disease
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A novel series of hybrid arylisoxazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase (ChE) inhibitory activity based on the modified Ellman's method. Among synthesized compounds, 5-(3-nitrophenyl)-N-{4-[(2-oxo-
- Akbarzadeh, Tahmineh,Edraki, Najmeh,Firuzi, Omidreza,Hariri, Roshanak,Mahdavi, Mohammad,Mirfazli, Seyedeh Sara,Rastegari, Arezoo,Saeedi, Mina
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- Discovery of heterocyclic carbohydrazide derivatives as novel selective fatty acid amide hydrolase inhibitors: design, synthesis and anti-neuroinflammatory evaluation
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Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat pain, inflammation, and other central nervous system disorders. Herein, a series of novel heterocyclic carbohydrazide derivatives were firstly designed by the classic scaffold-hopping strategy. Then, multi-steps synthesis and human FAAH enzyme inhibiting activity assays were conducted. Among them, compound 26 showed strong inhibition against human FAAH with IC50 of 2.8 μM. Corresponding docking studies revealed that the acyl hydrazide group of compound 26 well-occupied the acyl-chain binding pocket. It also exhibited high selectivity towards FAAH when comparing with CES2 and MAGL. Additionally, compound 26 effectively suppressed the LPS-induced neuroinflammation of microglial cells (BV2) via the reduction of interleukin-1β and tumor necrosis factor-α. Our results provided significative lead compounds for the further discovery of novel selective and safe FAAH inhibitors with potent anti-neuroinflammation activity.
- Hao, Qingjing,He, Mengting,Jiang, Kaixuan,Shang, Yanguo,Wang, Jinxin
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supporting information
(2020/04/08)
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- Novel substituted pyrazolo [1, 5-a] pyrimidine compound and preparation method and application thereof
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The invention provides a novel substituted pyrazolo [1, 5-a]pyrimidine compound and a preparation method and application thereof, and particularly relates to a pyrazolo [1, 5-a]pyrimidine-containing quinoline derivative shown as a general formula (I) and pharmaceutically acceptable salts thereof, and substituent groups X, Ar and A have meanings given in the specification. The invention also relates to a compound represented by the general formula (I), wherein the compound has a strong c-Met kinase inhibition effect. The invention also relates to application of the compound and the pharmaceutically acceptable salt thereof in preparation of drugs for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase, especially application in preparation of drugs for treating and/or preventing cancers.
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Paragraph 0091-0095
(2020/08/02)
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- Green and efficient synthesis of new pyrido[2,3-d]pyrimidine derivatives using Pd/SBA-15 as a nanocatalyst
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N-Fused heterocycles have received significant attention over the years as valuable compounds due to their biological and pharmaceutical activities. Heterogeneous catalysts such as periodic mesoporous materials have played an important role in the synthes
- Bardajee, Ghasem Rezanejade,Delbari, Akram Sadat,Ghaedi, Aseyeh,Hekmat, Shohreh
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- PYRIMIDINONE-CONTAINING COMPOUND, PREPARATION METHOD THEREOF, PHARMACEUTICAL COMPOSITION AND APPLICATION THEREOF
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Disclosed is a pyrimidinone-containing compound represented by formula I, a preparation method thereof, a pharmaceutical composition, and an application thereof. The pyrimidinone-containing compound of the present disclosure can be used as HIV-1 inhibitor
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Paragraph 0156-0157
(2021/01/22)
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- Ru-Catalyzed Chemo- and Enantioselective Hydrogenation of β-Diketones Assisted by the Neighboring Heteroatoms
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A highly chemo- and enantioselective hydrogenation of β-diketones was achieved by using [Ru(benzene)(S)-SunPhosCl]Cl for consistency in THF. The neighboring heteroatoms played important roles in guaranteeing the reactivity and controlling the chemoselectivity. These results suggested a potential approach for the clean and facile synthesis of functionalized chiral β-hydroxy ketones, which could otherwise be prepared through much less step-economic transformations.
- Li, Wanfang,Lu, Bin,Xie, Xiaomin,Zhang, Zhaoguo
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supporting information
p. 5509 - 5513
(2019/08/01)
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- Pyrazole amide derivatives as well as preparation method and application thereof
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The invention relates to pyrazole derivatives represented by a general formula I shown in the description, or a stereoisomer and tautomer of the pyrazole derivatives, a preparation method of the pyrazole derivatives, and an application of the of the pyraz
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Paragraph 0140-0143
(2019/05/16)
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- Substituted heterocyclic compound containing acylhydrazone skeleton as well as preparation method and application thereof (by machine translation)
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The invention discloses a substituted heterocyclic compound containing an acylhydrazone skeleton as well as a preparation method and application, of the substituted heterocyclic compound. The invention relates to the field, in particular to a substituted heterocyclic compound containing an acylhydrazone skeleton or a pharmaceutically acceptable salt, a pharmaceutical composition containing the compounds and medical application, in particular to an FAAH inhibitor, and application, in preparation of drugs for preventing or treating diseases related to FAAH, including depression, analgesia, cannabinoid use disorders and other related diseases. (by machine translation)
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Paragraph 0034-0037
(2019/09/14)
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- Discovery of 2-phenylthiazole-4-carboxylic acid, a novel and potent scaffold as xanthine oxidase inhibitors
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The xanthine oxidase (XO) plays an important role in producing uric acid, and therefore XO inhibitors are considered as one of the promising therapies for hyperuricemia and gout. We have previously reported a series of XO inhibitors with pyrazole scaffold to extend the chemical space of current XO inhibitors. Herein, we describe further structural optimization to explore the optimal heterocycle by replacing the thiazole ring of Febuxostat with 5 heterocycle scaffolds unexplored in this field. All of these efforts resulted in the identification of compound 8, a potent XO inhibitor (IC50 = 48.6 nM) with novel 2-phenylthiazole-4-carboxylic acid scaffold. Moreover, lead compound 8 exhibited hypouricemic effect in potassium oxonate-hypoxanthine-induced hyperuricemic mice. These results promote the understanding of ligand-receptor interaction and might help to design more promising XO inhibitors.
- Xu, Xue,Deng, Liming,Nie, Lu,Chen, Yueming,Liu, Yanzhi,Xie, Rongrong,Li, Zheng
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supporting information
p. 525 - 528
(2019/01/09)
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- APELIN RECEPTOR AGONISTS AND METHODS OF USE THEREOF
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Provided herein are agonists of the apelin receptor for the treatment of disease. The compounds disclosed herein are useful for the treatment of a range of cardiovascular, renal and metabolic conditions.
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Paragraph 0638-0639
(2019/02/25)
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- Synthesis, biological evaluation and in silico modelling studies of 1,3,5-trisubstituted pyrazoles carrying benzenesulfonamide as potential anticancer agents and selective cancer-associated hCA IX isoenzyme inhibitors
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Inhibition of carbonic anhydrases (CAs, EC 4.2.1.1) has clinical importance for the treatment of several diseases. They participate in crucial regulatory mechanisms for balancing intracellular and extracellular pH of the cells. Among CA isoforms, selectiv
- Yamali, Cem,Gul, Halise Inci,Ece, Abdulilah,Bua, Silvia,Angeli, Andrea,Sakagami, Hiroshi,Sahin, Ertan,Supuran, Claudiu T.
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- Hydroxamic Acid-Based Histone Deacetylase (HDAC) inhibitors bearing a pyrazole scaffold and a cinnamoyl linker
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Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms are also implicated in the insurgence and development of cancer. Patterns of the epigenetic component in
- Zagni, Chiara,Rescifina, Antonio,Citarella, Andrea,Maugeri, Alessandro,Navarra, Michele,Scala, Angela,Piperno, Anna,Micale, Nicola,Oussama, Mahjoub
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- Substituted heterocyclic compound containing urea skeleton and preparation method and application of substituted heterocyclic compound
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The invention discloses a substituted heterocyclic compound containing a urea skeleton and a preparation method and application of the substituted heterocyclic compound, and relates to the field of pharmaceutical chemistry, in particular to the substituted heterocyclic compound containing the urea skeleton or pharmaceutically acceptable salt of the substituted heterocyclic compound, a pharmaceutical composition containing the compounds and medical application of the compounds. Particularly, the invention relates to application of the substituted heterocyclic compound as an FAAH inhibitor in preparing drugs for preventing or treating diseases associated with FAAH, such as depression, analgesia, cannabinoid using disorders and other related diseases.
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Paragraph 0039-0042; 0070-0073
(2019/10/01)
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- Design, synthesis and structure-based optimization of novel isoxazole-containing benzamide derivatives as FtsZ modulators
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Antibiotic resistance among clinically significant bacterial pathogens is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. Utilizing computational docking method and structure-based optimization strategy, we rationally designed and synthesized two series of isoxazol-3-yl- and isoxazol-5-yl-containing benzamide derivatives that targeted the bacterial cell division protein FtsZ. Evaluation of their activity against a panel of Gram-positive and -negative pathogens revealed that compounds B14 and B16 that possessed the isoxazol-5-yl group showed strong antibacterial activity against various testing strains, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. aureus. Further molecular biological studies and docking analyses proved that the compound functioned as an effective inhibitor to alter the dynamics of FtsZ self-polymerization via a stimulatory mechanism, which finally terminated the cell division and caused cell death. Taken together, these results could suggest a promising chemotype for development of new FtsZ-targeting bactericidal agent.
- Bi, Fangchao,Song, Di,Zhang, Nan,Liu, Zhiyang,Gu, Xinjie,Hu, Chaoyu,Cai, Xiaokang,Venter, Henrietta,Ma, Shutao
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- Discovery of 1,5-Diphenylpyrazole-3-Carboxamide Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors
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Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol, which is implicated in many physiological processes. Beyond the possible utilization of MA
- Aghazadeh Tabrizi, Mojgan,Baraldi, Pier Giovanni,Baraldi, Stefania,Ruggiero, Emanuela,De Stefano, Lucia,Rizzolio, Flavio,Di Cesare Mannelli, Lorenzo,Ghelardini, Carla,Chicca, Andrea,Lapillo, Margherita,Gertsch, Jürg,Manera, Clementina,Macchia, Marco,Martinelli, Adriano,Granchi, Carlotta,Minutolo, Filippo,Tuccinardi, Tiziano
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p. 1340 - 1354
(2018/02/17)
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- FIVE-MEMBERED HETEROCYCLIC AMIDES WNT PATHWAY INHIBITOR
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The present invention discloses a five-membered heterocyclic amide WNT pathway inhibitor, which belongs to a compound that regulates the activity of a Wnt signaling pathway, and provides a method for preparing such a compound, and the use of such a compound in preparing a medicament that antagonizes the Wnt signaling pathway. The five-membered heterocyclic amide WNT pathway inhibitor provided by the invention has a remarkable anti-tumor activity based on a target-based rational drug design of, and can be used for the development of a new generation of Wnt pathway inhibitors, and has a great clinical application value and considerable market potential.
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Paragraph 0101; 0111-0113
(2018/10/19)
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- Synthetic method of OLED material intermediate benzoyl pyrimidine compound
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The invention discloses a synthetic method of an OLED material intermediate benzoyl pyrimidine compound. The synthetic method comprises the following steps: mixing alkali, a solvent I as well as substituent acetophenone and oxalic acid diester which are u
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Paragraph 0084; 0085; 0097; 0109; 0114
(2018/07/15)
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- Biphenyl heterocyclic derivatives, their preparation and their use as medicaments (by machine translation)
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The present invention relates to a novel biphenyl heterocyclic derivative represented by a general formula (I) and a preparation method thereof and use of a pharmaceutical composition containing the derivative for preparation of a drug for treating diabetes. The biphenyl heterocyclic derivative has extremely excellent hypoglycemic activity in vivo, and excellent in vivo safety and low liver toxicity risk of the compound having such a structure are unexpectedly found, and the novel biphenyl heterocyclic derivative may be used for preventing or treating diabetes.
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Paragraph 0348-0351
(2018/06/21)
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- Anti-inflammatory Exploration of Sulfonamide Containing Diaryl Pyrazoles with Promising COX-2 Selectivity and Enhanced Gastric Safety Profile
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Novel sulfonamide containing diaryl pyrazoles were synthesized and were subsequently tested for their in vitro cyclooxygenase inhibitory assay. Compounds that showed promising in vitro COX-2 IC50 values and selectivity indices were then evaluat
- Pavase, Laxmikant S.,Mane, Dhananjay V.,Baheti, Kamalkishor G.
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p. 913 - 922
(2018/02/12)
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- Fragment-based lead generation of 5-phenyl-1H-pyrazole-3-carboxamide derivatives as leads for potent factor xia inhibitors
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FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors' lead discovery. After repla
- Wei, Qunchao,Zheng, Zhichao,Zhang, Shijun,Zheng, Xuemin,Meng, Fancui,Yuan, Jing,Xu, Yongnan,Huang, Changjiang
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- Pyrrolone Derivatives as Intracellular Allosteric Modulators for Chemokine Receptors: Selective and Dual-Targeting Inhibitors of CC Chemokine Receptors 1 and 2
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The recent crystal structures of CC chemokine receptors 2 and 9 (CCR2 and CCR9) have provided structural evidence for an allosteric, intracellular binding site. The high conservation of residues involved in this site suggests its presence in most chemokine receptors, including the close homologue CCR1. By using [3H]CCR2-RA-[R], a high-affinity, CCR2 intracellular ligand, we report an intracellular binding site in CCR1, where this radioligand also binds with high affinity. In addition, we report the synthesis and biological characterization of a series of pyrrolone derivatives for CCR1 and CCR2, which allowed us to identify several high-affinity intracellular ligands, including selective and potential multitarget antagonists. Evaluation of selected compounds in a functional [35S]GTPγS assay revealed that they act as inverse agonists in CCR1, providing a new manner of pharmacological modulation. Thus, this intracellular binding site enables the design of selective and multitarget inhibitors as a novel therapeutic approach.
- Ortiz Zacarías, Natalia V.,Van Veldhoven, Jacobus P. D.,Portner, Laura,Van Spronsen, Eric,Ullo, Salviana,Veenhuizen, Margo,Van Der Velden, Wijnand J. C.,Zweemer, Annelien J. M.,Kreekel, Roy M.,Oenema, Kenny,Lenselink, Eelke B.,Heitman, Laura H.,Ijzerman, Adriaan P.
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p. 9146 - 9161
(2018/10/24)
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- Synthesis and cellular bioactivities of novel isoxazole derivatives incorporating an arylpiperazine moiety as anticancer agents
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In our endeavour towards the development of effective anticancer therapeutics, a novel series of isoxazole-piperazine hybrids were synthesized and evaluated for their cytotoxic activities against human liver (Huh7 and Mahlavu) and breast (MCF-7) cancer ce
- ?al??kan, Burcu,?bi?, Kübra,Banoglu, Erden,Sinoplu, Esra,Akhan Güzelcan, Ece,?etin Atalay, Rengül
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p. 1352 - 1361
(2018/11/21)
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- COMPOUNDS, COMPOSITIONS, AND METHODS FOR INCREASING CFTR ACTIVITY
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The invention encompasses compounds such as compounds having the Formula (I) or (II), compositions thereof, and methods of modulating CFTR activity. The invention also encompasses methods of treating a condition associated with CFTR activity or condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of a disclosed compound.
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Paragraph 0195
(2017/01/23)
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- Fatty Acid Cysteine-Based Conjugates and Their Use in Treating Medical Disorders
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The invention relates to fatty acid cysteine-based conjugates, compositions comprising a fatty acid cysteine-based conjugates, and methods for using such conjugates and compositions to treat disease, such as a disease caused by dysregulation of autophagy
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Paragraph 0297; 0298
(2018/01/04)
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- Design, synthesis and evaluation of aromatic heterocyclic derivatives as potent antifungal agents
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To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (1), a series of aromatic heterocyclic derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Many of the target compounds showed good inhibitory activity against Candida albicans and Cryptococcus neoformans. In particular, the isoxazole nuclei were more suited for improving the activity against Aspergillus spp. Among these compounds, 2-F substituted analogues 23g and 23h displayed the most remarkable in vitro activity against Candida spp., C. neoformans, A. fumigatus and fluconazole-resistant C.alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and voriconazole. Notably, the compounds 23g and 23h exhibited low inhibition profiles for various isoforms of human cytochrome P450 and excellent blood plasma stability.
- Zhao, Shizhen,Zhang, Xiangqian,Wei, Peng,Su, Xin,Zhao, Liyu,Wu, Mengya,Hao, Chenzhou,Liu, Chunchi,Zhao, Dongmei,Cheng, Maosheng
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- Regio-specific synthesis of new 1-(tert-butyl)-1H-pyrazolecarboxamide derivatives
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Regio-specific and non-regiospecific condensation reactions on 1,3-dicarbonyl compounds rendered 1,3,5-trisubstituted pyrazoles. Herein, the control of regio-specificity was a significant improvement in pyrazole research. A high yield acylation of poorly
- Ruatta, Santiago Matías,Murguía, Marcelo César,Ramírez de Arellano, Carmen,Fustero, Santos
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supporting information
p. 2441 - 2444
(2017/06/05)
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- Synthesis of 3-n-phenylthiocarbamoyl-2-butenamides from 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione in aqueous medium at room temperature
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Background: Earlier we found that the reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene- 2,3-dione (1) with primary aromatic amines, secondary aliphatic amines and N,N'-dinucleophiles such as 1-aminoguanidine, guanidine, urea, and 1,2-phenylenediamine in ethanol or acetic acid at high temperature gave the substituted thiophenes, amide and heterocyclic derivatives that have Nphenylthiocarbamoyl group, respectively. As a part of our studies on the intermediate 1 in relation to the synthesis of thioamides in aqueous medium, we now report the reactions of 1 with amines at room temperature in the THF-H2O (1:1) system. The reaction of 1 with primary and secondary aliphatic amines, N,N'-dinucleophiles such as hydrazine and guanidine and tertiary aromatic and aliphatic amines led to 3-N-phenylthiocarbamoyl-2-butenamides 2a-n. Method: In general, to a stirred solution of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) (1.0 mmol) in THF/H2O (1:1) was added each of the amines (1.0 mmol) (piperazine and DABCO 0.5 mmol) at room temperature. The reaction mixture was then stirred for 3-6 h. The progress of the reaction was monitored by TLC (eluent AcOEt/hexane 2:1). The resulting solid was separated by filtration and was recrystallized from a suitable solvent to give 2a-n. The structures of 2a-n were deduced from their elemental analyses and IR, 1H, 13C NMR spectroscopic and mass spectrometric data. Results: Reactions of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) with primary aliphatic amines, N,N'-dinucleophiles such as hydrazine and guanidine and secondary aliphatic amines under mild conditions in THF/H2O (1:1) afforded the corresponding N-alkyl and N,N-dialkyl 3-N-phenylthiocarbamoyl- 2-butenamides (2a-g and 2h-j) and 1,4-bis(3-N-phenylthiocarbamoyl-2-butenoyl)piperazine (2k). In addition, the reaction of 1 with tertiary aromatic and aliphatic amines in the same conditions led to stable 1,4-diionic nitrogen betaines 2l-n. These showed the nucleophilic attacks of primary and secondary aliphatic amines, N,N'-dinucleophiles and tertiary aromatic and aliphatic amines on thioesteric carboxyl group (C-2) of the thiophene-2,3-dione ring (1), due to the extremely high reactivity of the thioesteric carboxyl group. Conclusion: In conclusion, we have described a convenient route for the synthesis of 3-N-phenylthiocarbamoyl- 2-butenamide derivatives (2a-n) from 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3- dione (1) with primary and secondary aliphatic amines, N,N'-dinucleophiles and tertiary aromatic and aliphatic amines in medium to good yields. The advantage of the present procedure is that the reaction is performed in aqueous medium at room temperature by simple mixing of the starting materials.
- Hassan, Kabirifard,Samaneh, Akbari,Nazanin, Mousavi,Amin Simin, Mokhtari
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p. 503 - 509
(2017/08/29)
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- Design, synthesis and biological evaluation of 1H-pyrazole-5-carboxamide derivatives as potential fungicidal and insecticidal agents
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A series of novel 1H-pyrazole-5-carboxamide compounds containing the phenyl thiazole moiety were designed and synthesized by a facile method, and their structures were characterized by 1H NMR, mass spectrometry and elemental analysis. Bioassay results showed that most of the title compounds showed potent fungicidal activities against Erysiphe graminis and insecticidal activity against Aphis fabae. Especially, compound 9b has EC50 values of 3.04 mg/L against Erysiphe graminis, of which the fungicidal activity is better than that of the commercial fungicide Thifluzamide and Azoxystrobinare; compound 9l has LC50 values of 3.81 mg/L against Aphis fabae, which was comparable with the commercial insecticide Tolfenpyrad. It is suggested that 1H-pyrazole-5-carboxamide compounds containing the phenyl thiazole moiety could be considered as a precursor structure for further design of pesticides. Graphical Abstract: A series of novel 1H-pyrazole-5-carboxamide compounds containing the phenyl thiazole moiety were designed and synthesized by a facile method, and their structures were characterized by 1H NMR, mass spectrometry and elemental analysis. Bioassay results showed that most of the title compounds showed potent fungicidal activities against Erysiphe graminis and insecticidal activity against Aphis fabae. Especially, compound 9b has EC50 values of 3.04 mg/L against Erysiphe graminis, of which the fungicidal activity is better than that of the commercial fungicide Thifluzamide and Azoxystrobinare; compound 9l has LC50 values of 3.81 mg/L against Aphis fabae, which was comparable with the commercial insecticide Tolfenpyrad. It is suggested that 1H-pyrazole-5-carboxamide compounds containing the phenyl thiazole moiety could be considered as a precursor structure for further design of pesticides.[Figure not available: see fulltext.]
- Huang, Danling,Huang, Mingzhi,Liu, Weidong,Liu, Aiping,Liu, Xingping,Chen, Xiaoyang,Pei, Hui,Sun, Jiong,Yin, Dulin,Wang, Xiaoguang
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p. 2053 - 2061
(2017/09/30)
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- Design, synthesis and Structure-activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes
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The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.
- Li, Zheng,Qiu, Qianqian,Xu, Xue,Wang, Xuekun,Jiao, Lei,Su, Xin,Pan, Miaobo,Huang, Wenlong,Qian, Hai
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supporting information
p. 246 - 257
(2016/03/08)
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- FATTY ACID CYSTEAMINE CONJUGATES OF CFTR MODULATORS AND THEIR USE IN TREATING MEDICAL DISORDERS
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The invention relates to fatty acid cysteamine conjugates of a CFTR modulator, compositions comprising a fatty acid cysteamine conjugate of a CFTR modulator, and methods for using such conjugates and compositions to treat disease, such as a disease caused
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Paragraph 00226
(2016/06/14)
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- ISOXAZOLE COMPOUNDS AND METHODS FOR THE TREATMENT OF CYSTIC FIBROSIS
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The invention relates to a compound of Formula (I) and methods of treating cystic fibrosis comprising the step of administering a therapeutically effective amount of a compound of Formula (I) or II to a patient in need thereof: Formula (I) and Formula (II). The invention relates to the use of substituted oxazole and substituted thiazole compounds in the treatment of cystic fibrosis transmembrane conductance regulator (CFTR) mediated diseases.
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Page/Page column 36
(2016/04/26)
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- Synthesis and T-type calcium channel-blocking effects of aryl(1,5-disubstituted-pyrazol-3-yl)methyl sulfonamides for neuropathic pain treatment
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A novel series of aryl(1,5-disubstituted pyrazol-3-yl)methyl sulfonamide derivatives was designed, synthesized, and evaluated for T-type calcium channel (α1Gand α1H) inhibitory activity. We identified several compounds, 9a, 9b, 9g, and 9h that displayed good T-type channel inhibitory potency with low hERG channel and CYP450 inhibition. Among them, 9a and 9b exhibited neuropathic pain alleviation effects in mechanical and cold allodynia induced in the SNL rat model. Compounds 9a and 9b displayed better efficacy than mibefradil and gabapentin against cold allodynia. In particular, compound 9a seemed to be valuable as shown fast acting performance in mechanical neuropathic pain model.
- Kim, Jung Hyun,Keum, Gyochang,Chung, Hesson,Nam, Ghilsoo
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p. 665 - 672
(2016/08/19)
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- LOCALLY BIOAVAILABLE DRUGS
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Drugs have been designed and developed with a structural motif allowing local bioavailability in the target organ but that are not broadly distributed at a concentration sufficient to illicit toxic side effects in non-targeted organs. The structural motif
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- Simple and efficient syntheses of novel benzo[4,5]imidazo[1,2-a]pyridine derivatives
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A novel series of benzo[4,5]imidazo[1,2-a]pyridine derivatives is synthesized through the reaction of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile and different ethyl 2,4-dioxo-4-arylbutanoate derivatives in the presence of piperidine in refluxing EtOH. All the products are easily prepared within 25-45 min in good to excellent yields.
- Goli-Garmroodi, Fereshteh,Omidi, Marzieh,Saeedi, Mina,Sarrafzadeh, Farhad,Rafinejad, Ali,Mahdavi, Mohammad,Bardajee, Ghasem Rezanejade,Akbarzadeh, Tahmineh,Firoozpour, Loghman,Shafiee, Abbas,Foroumadi, Alireza
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p. 743 - 746
(2015/01/30)
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