- Novel arylcarbamate-N-acylhydrazones derivatives as promising BuChE inhibitors: Design, synthesis, molecular modeling and biological evaluation
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A novel series of arylcarbamate-N-acylhydrazones derivatives have been designed and synthesized as potential anti-cholinesterase agents. In vitro studies revealed that these compounds demonstrated selective for butyrylcholinesterase (BuChE) with potent inhibitory activity. The compounds 10a-d, 12b and 12d were the most potent BuChE inhibitors with IC50 values of 0.07–2.07 μM, highlighting the compound 10c (IC50 = 0.07 μM) which showed inhibitory activity 50 times greater than the reference drug donepezil (IC50 = 3.54 μM). The activity data indicates that the position of the carbamate group in the aromatic ring has a greater influence on the inhibitory activity of the derivatives. The enzyme kinetics studies indicate that the compound 10c has a non-competitive inhibition against BuChE with Ki value of 0.097 mM. Molecular modeling studies corroborated the in vitro inhibitory mode of interaction and show that compound 10c is stabilized into hBuChE by strong hydrogen bond interaction with Tyr128, π-π stacking interaction with Trp82 and CH?O interactions with His438, Gly121 and Glu197. Based on these data, compound 10c was identified as low-cost promising candidate for a drug prototype for AD treatment.
- Yamazaki, Diego A.S.,Rozada, Andrew M.F.,Baréa, Paula,Reis, Elaine C.,Basso, Ernani A.,Sarragiotto, Maria Helena,Seixas, Flávio A.V.,Gauze, Gisele F.
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- Discovery of an Orally Efficacious MYC Inhibitor for Liver Cancer Using a GNMT-Based High-Throughput Screening System and Structure-Activity Relationship Analysis
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Glycine-N-methyl transferase (GNMT) downregulation results in spontaneous hepatocellular carcinoma (HCC). Overexpression of GNMT inhibits the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is a potential approach for anti-HCC therapy. Herein, we used Huh7 GNMT promoter-driven screening to identify a GNMT inducer. Compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure-activity relationship analysis and found a potent GNMT inducer, K117. K117 inhibited Huh7 cell growth in vitro and xenograft in vivo. Oral administration of a dosage of K117 at 10 mpk (milligrams per kilogram) can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib at a dosage of 25 mpk. A mechanistic study revealed that K117 is an MYC inhibitor. Ectopic expression of MYC using CMV promoter blocked K117-mediated MYC inhibition and GNMT induction. Overall, K117 is a potential lead compound for HCC- and MYC-dependent cancers.
- Kant, Rajni,Yang, Ming-Hui,Tseng, Chih-Hua,Yen, Chia-Hung,Li, Wei-You,Tyan, Yu-Chang,Chen, Marcelo,Tzeng, Cherng-Chyi,Chen, Wei-Cheng,You, Kaiting,Wang, Wen-Chieh,Chen, Yeh-Long,Chen, Yi-Ming Arthur
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p. 8992 - 9009
(2021/07/19)
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- Preclinical evaluation of 1,2,4-triazole-based compounds targeting voltage-gated sodium channels (VGSCs) as promising anticonvulsant drug candidates
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Epilepsy is a chronic neurological disorder affecting nearly 65–70 million people worldwide. Despite the observed advances in the development of new antiepileptic drugs (AEDs), still about 30–40% of patients cannot achieve a satisfactory seizure control. In our current research, we aimed at using the combined results of radioligand binding experiments, PAMPA-BBB assay and animal experimentations in order to design a group of compounds that exhibit broad spectrum of anticonvulsant activity. The synthesized 4-alkyl-5-substituted-1,2,4-triazole-3-thione derivatives were primarily screened in the maximal electroshock-induced seizure (MES) test in mice. Next, the most promising compounds (17, 22) were investigated in 6 Hz (32 mA) psychomotor seizure model. Protective effect of compound 22 was almost similar to that of levetiracetam. Moreover, these compounds did not induce genotoxic and hemolytic changes in human cells as well as they were characterized by low cellular toxicity. Taking into account the structural requirements for good anticonvulsant activity of 4-alkyl-5-aryl-1,2,4-triazole-3-thiones, it is visible that small electron-withdrawing substituents attached to phenyl ring have beneficial effects both on affinity towards VGSCs and protective activity in the animal models of epilepsy.
- Kaproń, Barbara,?uszczki, Jarogniew J.,Siwek, Agata,Karcz, Tadeusz,Nowak, Gabriel,Zagaja, Miros?aw,Andres-Mach, Marta,Stasi?owicz, Anna,Cielecka-Piontek, Judyta,Kocki, Janusz,Plech, Tomasz
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- Design, synthesis, and in vitro evaluation of novel 1,3,4-oxadiazolecarbamothioate derivatives of Rivastigmine as selective inhibitors of BuChE
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Rivastigmine has been prescribed for the therapy of Alzheimer’s disease (AD) symptoms. This drug is classified in the carbamate derivative group that has dual activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). According to the structure of Rivastigmine and its performance, a new series of 5-aryl-1,3,4-oxadiazole-2-carbamothioate compounds I–XI was synthesized using structure-based drug discovery approaches. For this purpose a set of these compounds were designed with computational docking method and their interactions with amino acid residues in the active sites of AChE and BuChE checked out. The structures of synthesized compounds were established by physicochemical and spectroscopic methods. The carbamoyl moiety of Rivastigmine structure was modified to carbamothioate and the effects of 1,3,4-oxadiazole heterocycle as a pharmacophoric nucleus were investigated. The potential of the synthesized compounds I–XI was evaluated against two most known agents of AD (AChE and BuChE) to determine their IC50 values. The results of the docking showed the range of binding affinity for the best poses of ten individual conformers for any compounds (I–XI) was between ?7.81 (VI) and ?6.75 (II) kcal/mol. The results of biological experiments displayed that most synthetic compounds (I–VIII) showed moderate to excellent selective activity range against BuChE (0.51–69.44 μM). In vitro cytotoxicity evaluation of these compounds (I–XI) by MTT assay on human dermal fibroblast (HDF) cell line exhibited no activity against HDF. The compound VI [S-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl) ethyl(methyl)carbamothioate] showed the most stable binding affinity (?7.81 kcal/mol) and the lowest IC50 value (0.51 μM) in comparison with Rivastigmine with 7.72 μM and Donepezil with 5.20 μM against BuChE.
- Fallah, Akram,Mohanazadeh, Farajollah,Safavi, Maliheh
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p. 341 - 355
(2019/12/30)
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- Synthesis and structure-activity relationship studies of hydrazide-hydrazones as inhibitors of laccase from trametes versicolor
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A series of hydrazide-hydrazones 1-3, the imine derivatives of hydrazides and aldehydes bearing benzene rings, were screened as inhibitors of laccase from Trametes versicolor. Laccase is a copper-containing enzyme which inhibition might prevent or reduce the activity of the plant pathogens that produce it in various biochemical processes. The kinetic and molecular modeling studies were performed and for selected compounds, the docking results were discussed. Seven 4-hydroxybenzhydrazide (4-HBAH) derivatives exhibited micromolar activity Ki = 24-674 μM with the predicted and desirable competitive type of inhibition. The structure-activity relationship (SAR) analysis revealed that a slim salicylic aldehyde framework had a pivotal role in stabilization of the molecules near the substrate docking site. Furthermore, the presence of phenyl and bulky tert-butyl substituents in position 3 in salicylic aldehyde fragment favored strong interaction with the substrate-binding pocket in laccase. Both 3- and 4-HBAH derivatives containing larger 3-tert-butyl-5-methyl- or 3,5-di-tert-butyl-2-hydroxy-benzylidene unit, did not bind to the active site of laccase and, interestingly, acted as non-competitive (Ki = 32.0 μM) or uncompetitive (Ki = 17.9 μM) inhibitors, respectively. From the easily available laccase inhibitors only sodium azide, harmful to environment and non-specific, was over 6 times more active than the above compounds.
- Giurg, Miros?aw,Maniak, Halina,Matyja, Konrad,Talma, Micha?,Trusek, Anna
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- Synthesis of novel xanthene based analogues: Their optical properties, jack bean urease inhibition and molecular modelling studies
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In this work, a series of the rhodamine 6G based derivatives 5a-5g, were synthesized. The structural framework of the synthesized compounds was established by using 1H NMR, 13C NMR, FT-IR, and LC-MS analytical methods. The spectroscopic properties of the target compounds were determined by using absorption and fluorescence study in four different solvents. Furthermore, the synthesized derivatives were assessed for in-vitro screening against jack bean urease inhibition and in-silico molecular docking study. The result reveals that all the compounds exhibit good urease inhibitory activity against this enzyme but among the series, the compound 5a & 5c with an IC50 values of 0.1108 ± 0.0038 μM and 0.1136 ± 0.0295 μM shows to be most auspicious inhibitory activity compared to a standard drug (Thiourea) having IC50 value 4.7201 ± 0.0546 μM. Subsequently, the molecular docking experiment was analysed to distinguish the enzyme-inhibitor binding interaction.
- Dige, Nilam C.,Hassan, Mubashir,Lee, Ki Hwan,Mahajan, Prasad G.,Raza, Hussain,Seo, Sung-Yum,Vanjare, Balasaheb D.
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- New imidazo[2,1-: B] thiazole-based aryl hydrazones: Unravelling their synthesis and antiproliferative and apoptosis-inducing potential
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Herein, we have designed and synthesized new imidazo[2,1-b]thiazole-based aryl hydrazones (9a-w) and evaluated their anti-proliferative potential against a panel of human cancer cell lines. Among the synthesized compounds, 9i and 9m elicited promising cytotoxicity against the breast cancer cell line MDA-MB-231 with IC50 values of 1.65 and 1.12 μM, respectively. Cell cycle analysis revealed that 9i and 9m significantly arrest MDA-MB-231 cells in the G0/G1 phase. In addition, detailed biological studies such as annexin V-FITC/propidium iodide, DCFH-DA, JC-1 and DAPI staining assays revealed that 9i and 9m triggered apoptosis in MDA-MB-213 cells. Overall, the current work demonstrated the cytotoxicity and apoptosis-inducing potential of 9i and 9m in breast cancer cells and suggested that they could be explored as promising antiproliferative leads in the future. This journal is
- Babu, Bathini Nagendra,Devi, Ganthala Parimala,Kamal, Ahmed,Kumar, C. Ganesh,Rani Routhu, Sunitha,Shareef, Mohd Adil
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p. 1178 - 1184
(2020/11/03)
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- Efficient Synthesis of 1,4-Bis(5-aryl-1,3,4-oxadiazol-2-yl)-2,3,5,6-tetrafluorobenzenes
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Abstract: An efficient acid-catalyzed condensation between substituted benzohydrazides and 2,3,5,6-tetrafluoroterephthalic acid to form 1,4-bis(5-aryl-1,3,4-oxadiazol-2-yl)-2,3,5,6-tetrafluorobenzenes is reported. The products were isolated in 74–87% yield and were characterized by 1H NMR, IR, and mass spectra.
- Dhotre, B. K.,Khandebharad, A. U.,Pathan, A.,Raut, S. V.
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p. 1324 - 1326
(2020/10/02)
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- Aromatic acyl hydrazone derivative and application thereof as NA inhibitor
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The invention relates to an aromatic acyl hydrazone derivative as shown in a structural formula I, pharmaceutically acceptable salt and a pharmaceutical composition thereof, and application of the aromatic acyl hydrazone derivative and the pharmaceutically acceptable salt and the pharmaceutical composition in preparation of an influenza virus neuraminidase inhibitor, wherein R is one of trifluoromethyl, nitryl, 3-methyl-4-nitryl, 3-hydroxyl-4-nitryl, 3-nitryl-4-hydroxyl, hydroxyl, dihydroxyl, dinitryl, 3-methoxy-4-hydroxyl or trihydroxyl; Y is selected from hydroxyl, dihydroxyl, 2-hydroxyl-3-methoxy, 2-hydroxyl-4-methoxy,2-hydroxyl-5-methoxy,2-hydroxyl-6-methoxy,3-hydroxyl-2-methoxy,3-hydroxyl-4-methoxy,3-hydroxyl-5-methoxy,3-hydroxyl-6-methoxy,4-hydroxyl-2-methoxy,4-hydroxyl-3-methoxy,4-hydroxyl-3,5-dimethoxy, trihydroxyl, 4-hydroxyl-3-ethoxy, or 4-hydroxyl-3,5-dimethoxy; w is selected from CH or N; and z is selected from CH or N.
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Paragraph 0039; 0044-0046; 0157-0161
(2020/12/30)
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- A pH-sensitive near-infrared fluorescent probe with alkaline p: K a for chronic wound monitoring in diabetic mice
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A pH-sensitive near-infrared fluorescent probe with alkaline pKa, AlkaP-1, was developed by incorporating a benzoyl hydrazine group into a cyanine dye. The significant fluorescence changes in the alkaline regions enable the probe to monitor the alkalization process from acute wounds to chronic wounds in diabetic mice.
- Mai, Hengtang,Wang, Yu,Li, Shuang,Jia, Ruizhen,Li, Sixian,Peng, Qian,Xie, Yan,Hu, Xiang,Wu, Song
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supporting information
p. 7374 - 7377
(2019/06/27)
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- 1-(2-Hydroxybenzoyl)-thiosemicarbazides are promising antimicrobial agents targeting D-alanine-D-alanine ligase in bacterio
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The bacterial cell wall and the enzymes involved in peptidoglycan synthesis are privileged targets for the development of novel antibacterial agents. In this work, a series of 1-(2-hydroxybenzoyl)-thiosemicarbazides inhibitors of D-Ala-D-Ala ligase (Ddl) were designed and synthesized in order to target resistant strains of bacteria. Among these, the 4-(3,4-dichlorophenyl)-1-(2-hydroxybenzoyl)-3-thiosemicarbazide 29 was identified as a potent Ddl inhibitor with activity in the micromolar range. This compound, possessing strong antimicrobial activity including against multidrug resistant strains, was proven to act through a bactericidal mechanism and demonstrated very low cytotoxicity on THP-1 human monocytic cell line. Inhibition of Ddl activity by 29 was confirmed in bacterio using UPLC-MS/MS by demonstrating an increase in D-Ala intracellular pools accompanied by a commensurate decrease in D-Ala-D-Ala. Further structure-activity relationships (SARs) studies provided evidence that the hydroxyl substituent in the 2-position (R1) of the benzoylthiosemicarbazide scaffold is essential for the enzymatic inhibition. This work thus highlights the 1-(2-hydroxybenzoyl)-thiosemicarbazide motif as a very promising tool for the development of novel antibacterial compounds acting through an interesting mechanism of action and low cytotoxicity.
- Ameryckx, Alice,Thabault, Léopold,Pochet, Lionel,Leimanis, Serge,Poupaert, Jacques H.,Wouters, Johan,Joris, Bernard,Van Bambeke, Fran?oise,Frédérick, Rapha?l
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supporting information
p. 324 - 338
(2018/10/15)
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- Design, synthesis, and evaluation of simple phenol amides as ERRγ agonists
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Herein we report the design and synthesis of a series of simple phenol amide ERRγ agonists based on a hydrazone lead molecule. Our structure activity relationship studies in this series revealed the phenol portion of the molecule to be required for activity. Attempts to replace the hydrazone with more suitable chemotypes led to a simple amide as a viable alternative. Differential hydrogen-deuterium exchange experiments were used to help understand the structural basis for binding to ERRγ and aid in the development of more potent ligands.
- Lin, Hua,Doebelin, Christelle,Patouret, Rémi,Garcia-Ordonez, Ruben D.,Ra Chang, Mi,Dharmarajan, Venkatasubramanian,Bayona, Claudia Ruiz,Cameron, Michael D.,Griffin, Patrick R.,Kamenecka, Theodore M.
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p. 1313 - 1319
(2018/03/21)
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- Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors
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A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58–84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2. However, size and position of the substituents affected enzyme inhibitions.. In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of ?64.92,-203.25 and ?140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values ?170.91, ?256.84 and ?235.97 kcal/mol, respectively.
- Nisa, Mehr-un,Munawar, Munawar A.,Iqbal, Amber,Ahmed, Asrar,Ashraf, Muhammad,Gardener, Qurra-tul-Ann A.,Khan, Misbahul A.
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supporting information
p. 396 - 406
(2017/07/10)
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- Synthesis and antioxidant activity of 1,3,4-oxadiazoles and their diacylhydrazine precursors derived from phenolic acids
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Eight 1,3,4-oxadiazole derivatives containing phenolic acid moieties (7a-h) and eight of their diacylhydrazine precursors (6a-h) were synthesized, characterized using spectroscopic methods and examined by scavenging of stable DPPH (2,2-diphenyl-1-picrylhydrazyl) radicals. The most potent phenolic 1,3,4-oxadiazoles showed better DPPH scavenging activity in comparison with their corresponding diacylhydrazine precursors as a result of participation of both aromatic rings and a 1,3,4-oxadiazole moiety in resonance stabilization of the formed phenoxyl radical. Four diacylhydrazines (6d, 6e, 6g, and 6h) and four 1,3,4-oxadiazoles (7d, 7e, 7g and 7h) with the best DPPH scavenging activity, were chosen for further evaluation of their antioxidant potential through various assays. The investigated compounds exerted pronounced ABTS radical scavenging capacity, moderate to good H2O2 scavenging properties and strong ferric ion reducing capacity. Further in vitro evaluation of the antioxidant properties of the most active compounds demonstrated their protective effects in normal lung fibroblasts MRC-5 against hydrogen peroxide induced oxidative stress. Diacylhydrazine 6h increased two times the activity of glutathione peroxidase in treated cells in comparison with a control sample and did not affect the superoxide dismutase activity.
- Mihailovi?, Nevena,Markovi?, Violeta,Mati?, Ivana Z.,Stanisavljevi?, Nemanja S.,Jovanovi?, ?ivko S.,Trifunovi?, Sne?ana,Joksovi?, Ljubinka
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p. 8550 - 8560
(2017/02/10)
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- Identification and preliminary structure–activity relationships of 1-Indanone derivatives as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors
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Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in the catabolism of tryptophan along with the kynurenine pathway which is involved in many human diseases including cancer, Alzheimer's disease, etc. In this study, compound 1 bearing a 1-Indanone scaffold was identified as a novel IDO1 inhibitor by structure-based virtual screening, with moderate to good enzymatic and cellular inhibitory activities. Also, surface plasmon resonance analysis validated the direct interaction between compound 1 and IDO1 protein. The preliminary SAR was further explored and the binding mode with IDO1 protein was predicted by experiment along with molecular docking. Subsequent ADME properties of these active compounds were analyzed in silico, and the results showed good pharmacokinetic efficiencies. We believe this study contributes a lot to the structural diversity for the future development of highly potent IDO1 inhibitors.
- Gao, Dingding,Li, Yingxia
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p. 3780 - 3791
(2017/06/13)
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- Four-gear ring metal platinum (II) complex phosphorescent luminescent materials
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The invention discloses four-gear ring metal platinum (II) phosphorescent luminescent materials as shown in a formula (I) in the specification, wherein a five-membered heterocyclic aromatic group Ar is as shown in the specification; Ar is selected from one of the following: 2H-1,2,3-triazole, X1=N, X2=N, X3=CH); 1H-1,2,3-triazole, X1=CH, X2=N, X3=N; 1,3,4-oxadiazole, X1=O, X2=C, X3=N; oxazole, X1=O, X2=C, X3=CH; or thiazole, X1=S, X2=C, X3=CH. One or more of the four-gear ring metal platinum (II) phosphorescent luminescent materials disclosed by the invention are applied to a luminescent layer of an organic illuminator. The four-gear ring metal platinum (II) phosphorescent luminescent materials disclosed by the invention have strong molecular rigidity, can effectively reduce energy consumed owing to molecular vibration, and have high phosphorescent quantum efficiency, good chemical stability and good heat stability.
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Paragraph 0048; 0050
(2017/11/16)
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- Development of hydroxy-based sphingosine kinase inhibitors and anti-inflammation in dextran sodium sulfate induced colitis in mice
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Sphingosine kinase (SphK)-catalyzed production of sphingosine-1-phosphate (S1P) regulates cell growth, survival and proliferation as well as inflammatory status in animals. In recent study we reported the N′-(3-(benzyloxy)benzylidene)-3,4,5-trihydroxybenzohydrazide scaffold as a potent SphK inhibitor. As a continuation of these efforts, 51 derivatives were synthesized and evaluated by SphK1/2 inhibitory activities for structure-activity relationship (SAR) study. Among them, 33 was identified as the most potent SphK inhibitor. Potency of 33 was also observed to efficiently decrease SphK1/2 expression in human colorectal cancer cells (HCT116) and significantly inhibit dextran sodium sulfate (DSS)-induced colitis as well as the decreased expression of interleukin (IL)-6 and cyclooxygenase-2 (COX-2) in mouse models. Collectively, 33 was validated as an effective SphK inhibitor, which can be served as anti-inflammatory agent to probably treat inflammatory bowel diseases in human.
- Xi, Meiyang,Ge, Jun,Wang, Xiaojian,Sun, Chenbin,Liu, Tianqi,Fang, Liang,Xiao, Qiong,Yin, Dali
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p. 3218 - 3230
(2016/07/06)
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- Epoxy resin bearing diacylhydrazine moiety as a degradable adhesive for traceless oxidative removal
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Bisphenols functionalized with diacylhydrazine moieties and ester groups were prepared from 5-hydroxyisophthalic acid by esterification and partial hydrazination, followed by oxidative coupling of the obtained hydrazide. Ester groups with long alkyl chains or polyether increased the solubility of bisphenols in the epoxy resin. The epoxy resin was cured by heating with bisphenols in the presence of a catalytic amount of imidazole, with more rapid curing observed for more soluble bisphenols. The cured resin, with Td5?≈?300?°C, decomposed rapidly when exposed to sodium hypochlorite solution. The above resin could be used as a strong and tough adhesive for metal and glass, whereas it can be easily removed by treatment with sodium hypochlorite solution without any trace. The observed dismantling rate positively correlated with bisphenol solubility.
- Oguri, Takahiro,Kawahara, Akie,Kihara, Nobuhiro
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- Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors
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A novel serie of escitalopram triazoles (60-88) and a tetrazole (89) have been synthesized and subjected to a study to establish the inhibitory potential of these compounds toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Some selectivity in inhibition has been observed. The 4-chlorophenyl- (75, IC50, 6.71 ± 0.25 μM) and 2-methylphenyl- (70, IC50, 9.52 ± 0.23 μM) escitalopram triazole derivatives depicted high AChE inhibition, while 2-fluorophenyl- (76, IC50 = 4.52 ± 0.17 μM) and 4-fluorophenyl- (78, IC50 = 5.31 ± 0.43 μM) have found to be excellent BChE inhibitors. It has also been observed that ortho, meta and para substituted electron donating groups increase the inhibition, while electron withdrawing groups reduce the inhibition. Docking analyses of inhibitors with AChE have depicted the binding energies for 70 and 75 as ΔGbind -6.42 and -6.93 kcal/mol, respectively, while ligands 76 and 78 have shown the binding affinity ΔGbind -9.04 and -8.51 kcal/mol, respectively, for BChE.
- Mehr-Un-Nisa,Munawar, Munawar A.,Chattha, Fauzia A.,Kousar, Samina,Munir, Jawaria,Ismail, Tayaba,Ashraf, Muhammad,Khan, Misbahul A.
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p. 6014 - 6024
(2015/11/11)
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- Heterocyclic compounds useful for kinase inhibition
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Provided herein are compounds useful for kinase inhibition.
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Page/Page column 84-85
(2016/04/02)
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- Microwave assisted synthesis of biologically active 4-hydroxy-N′- (phenylcarbonyl)-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide derivatives
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Microwave assisted synthesis of a series of 4-hydroxy-N′- (phenylcarbonyl)-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides from sodium saccharin is reported. Sodium o-benzosulfimide was N-alkylated with ethyl chloroacetate followed by base catalyzed ring expansion to six membered 1,2-benzothiazine through Gabriel-Coleman type rearrangement yielding ethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide. It was later condensed with a series of benzohydrazides synthesized from various carboxylic acids to get the title compounds. All the synthesized compounds were subjected to preliminary evaluation for their biological activity against series of Gram positive, Gram negative bacteria and fungi. Some of the compounds showed marked activity against the selected microorganisms.
- Zaheer, Muhammad,Zia-Ur-Rehman, Muhammad,Rahman, Salma,Ahmed, Naveed,Chaudhary, Muhammad Nawaz
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p. 1492 - 1496
(2013/06/27)
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- Synthesis and antihyperlipidemic activity of some novel 4-(substitutedamino)-5-substituted-3-mercapto-(4H)-1,2,4-triazoles
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Hyperlipidemia is considered one of the key factors for cardiovascular diseases. Based on earlier work on a series of 5-alkyl-4-aryl-3-mercapto-(4H)-1, 2,4-triazoles, for further lead modification, a series of 4-(substituted)amino- 5-substituted-3-mercapto-(4H)-1,2,4-triazoles was designed. Target compounds were synthesized by the well known Hoggarth synthesis of substituted 1,2,4-triazoles. Synthesized compounds were screened for lipid lowering activity using the "Poloxamer 407 induced hyperlipidemia in rats" model at a dose of 100 mg/kg p. o. Compounds were found to alter serum lipid levels significantly. Most of the compounds significantly reduced serum cholesterol and triglyceride levels. Some of the compounds were found to reduce triglycerides and elevate high density lipoprotein (HDL) levels more than the standard drug atorvastatin (CAS 134523-03-8). Compounds with chloro substitution on aryl rings were found more active in reducing serum lipid levels than other substitutions. ECV ? Editio Cantor Verlag.
- Chhabria, Mahesh T.,Suhagia, Bhanubhai N.,Brahmkshatriya, Pathik S.,Raval, Priyesha M.
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p. 452 - 457
(2012/06/16)
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- New potent inhibitors of tyrosinase: Novel clues to binding of 1,3,4-thiadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2(3H)-thiones, 4-amino-1,2,4-triazole-5(4H)-thiones, and substituted hydrazides to the dicopper active site
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A series of 1,3,4-thiadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2(3H)-thiones, 4-amino-1,2,4-triazole-5(4H)-thiones, and substituted hydrazides were tailored and synthesized as new potent inhibitors of tyrosinase. The rationale for inhibitor design was based on the active site structural evidence from the crystal structures of bacterial tyrosinase and potato catechol oxidase enzymes. Kinetic and active site binding studies suggested mono-dentate binding of thiadiazole, oxadiazole, and triazole rings to the active site dicopper center of tyrosinase including hydrophobicity contributing to the potent inhibition. Kinetic plots showed mixed-type of inhibition by all 25 compounds. Substitutions at C3 of the triazole ring and C5 of the thiadiazole/oxadiazole rings were found to be playing a major role in the high binding affinity to tyrosinase. The current work may help develop new potent tyrosinase inhibitors against hyperpigmentation including potential insecticides.
- Ghani, Usman,Ullah, Nisar
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scheme or table
p. 4042 - 4048
(2010/08/06)
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- Antileishmanial activity screening of 5-nitro-2-heterocyclic benzylidene hydrazides
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A series of 53 nitro derivatives rationally designed were obtained by parallel synthesis and screened against Leishmania donovani. Six compounds exhibited IC50 values lower than standard drugs. Brief SAR analysis revealed that substitution is important to the activity. Nitrothiophene analogues were more potent than the nitrofuran ones. This was attributed to the ability of sulfur atoms in accommodating electrons from nitro group, which facilitate its reduction and therefore the formation of free radicals lethal to parasites.
- Rando, Daniela G.,Avery, Mitchell A.,Tekwani, Babu L.,Khan, Shabana I.,Ferreira, Elizabeth I.
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p. 6724 - 6731
(2008/12/22)
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- Inhibition of advanced protein glycation by 8-quinolinecarboxylic hydrazide
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Glycation of proteins is believed to be involved in the pathogenesis of diabetic complications, and thus the development of potent inhibitors of protein glycation is highly desirable. We tested the inhibitory effects of 12 hydrazide compounds against protein glycation and compared them with the effects of aminoguanidine (AG), a well-known inhibitor. When bovine serum albumin (BSA) was incubated with 100 mmol/l mannose for 10 days at 37°C in the presence and absence of hydrazide compounds or AG at 1 mmol/l, only p-anisic hydrazide inhibited Amadori product formation. On the other hand, 8 hydrazides as well as AG inhibited the formation of advanced glycation end products (AGEs). 8-Quinolinecarboxylic hydrazide (8-QCH), the most potent hydrazide, was more effective than AG. Neither 8-QCH nor AG affected the spontaneous decrease in Amadori products of preglycated BSA in the absence of sugar, but suppressed the spontaneous increase in AGEs from preglycated BSA, with higher potency of 8-QCH relative to AG. The results indicate that 8-QCH is a more potent inhibitor of AGE formation than AG and suggest that the inhibition mechanisms of 8-QCH and AG resemble each other.
- Miwa, Ichitomo,Tsugawa, Tohru,Koyasu, Katsuya,Terada, Yukimasa
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p. 314 - 320
(2007/10/03)
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