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Quinazoline

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https://www.readbyqxmd.com/read/27894242/indazolo-3-2-b-quinazolinones-attack-hepatocellular-carcinoma-hep3b-cells-by-inducing-mitochondrial-dependent-apoptosis-and-inhibition-of-nrf2-are-signaling-pathway
#1
Y Zhang, R Qiao, D He, Z Zhao, S Yang, H Zou, X Zhang, M Wu, J Chen, P Chen
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Genotoxic stress resistance in patients often contributes to poor clinical outcomes, and is intensively associated to the upregulation of Nrf2/ARE signaling pathway. In this study, we examined the connection between the anti-cancer activity of two novel indazolo[3,2-b]quinazolinone (IQ) derivatives, IQ-7 and IQ-12, and their effect on the Nrf2/ARE signaling pathway. The two compounds were shown to induce apoptosis and inhibit the Nrf2/ARE signaling pathway in Hep3B cells (human hepatoma cell line)...
November 28, 2016: Current Molecular Medicine
https://www.readbyqxmd.com/read/27886645/a-new-2-2-hydroxyphenyl-quinazolin-4-3h-one-derived-acylhydrazone-for-fluorescence-recognition-of-al-3
#2
Lijun Tang, Shuangli Ding, Keli Zhong, Shuhua Hou, Yanjiang Bian, Xiaomei Yan
A new 2-(2'-hydroxyphenyl)quinazolin-4(3H)-one derived acylhydrazone (QP) was designed and synthesized as a fluorescent sensor. In Tris∙HCl buffer (10mM, pH7.4)/ethanol (1/9, v/v) solution, QP exhibits a highly selective fluorescence response to Al(3+) over other metal ions with a significant blue-shifted and enhanced emission at 473nm. QP interacts with Al(3+) reversibly through a 1:2 binding ratio with a detection limit of 4.79×10(-8)M. Potential applicability of QP for Al(3+) detection in tap and lake water samples were also examined by 'proof-of-concept' experiments...
November 20, 2016: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/27863392/discovery-of-bpr1k871-a-quinazoline-based-multi-kinase-inhibitor-for-the-treatment-of-aml-and-solid-tumors-rational-design-synthesis-in-vitro-and-in-vivo-evaluation
#3
Yung Chang Hsu, Mohane Selvaraj Coumar, Wen-Chieh Wang, Hui-Yi Shiao, Yi-Yu Ke, Wen-Hsing Lin, Ching-Chuan Kuo, Chun-Wei Chang, Fu-Ming Kuo, Pei-Yi Chen, Sing-Yi Wang, An-Siou Li, Chun-Hwa Chen, Po-Chu Kuo, Ching-Ping Chen, Ming-Hsine Wu, Chen-Lung Huang, Kuei-Jung Yen, Yun-I Chang, John T-A Hsu, Chiung-Tong Chen, Teng-Kuang Yeh, Jen-Shin Song, Chuan Shih, Hsing-Pang Hsieh
The design and synthesis of a quinazoline-based, multi-kinase inhibitor for the treatment of acute myeloid leukemia (AML) and other malignancies is reported. Based on the previously reported furanopyrimidine 3, quinazoline core containing lead 4 was synthesized and found to impart dual FLT3/AURKA inhibition (IC50 = 127/5 nM), as well as improved physicochemical properties. A detailed structure-activity relationship study of the lead 4 allowed FLT3 and AURKA inhibition to be finely tuned, resulting in AURKA selective (5 and 7; 100-fold selective over FLT3), FLT3 selective (13; 30-fold selective over AURKA) and dual FLT3/AURKA selective (BPR1K871; IC50 = 19/22 nM) agents...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27863026/design-and-synthesis-of-selurampanel-a-novel-orally-active-and-competitive-ampa-receptor-antagonist
#4
David Orain, Engin Tasdelen, Samuel Haessig, Manuel Koller, Anne Picard, Celine Dubois, Kurt Lingenhoehl, Sandrine Desrayaud, Phillip Floersheim, David Carcache, Stephan Urwyler, Joerg Kallen, Henri Mattes
A series of potent quinazolinedione sulfonamide antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor were designed and synthesized. The structure-activity relationships (SAR) and in vivo activity of the series were investigated. In particular, compound 1 S (selurampanel; N-[7-isopropyl-6-(2-methylpyrazol-3-yl)-2,4-dioxo-1H-quinazolin-3-yl]methanesulfonamide) has shown excellent oral potency against maximal electroshock seizure (MES)-induced generalized tonic-clonic seizures in rodents as well as significant activity in patients suffering from various forms of epilepsy...
November 15, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27846451/sar-study-of-5-alkynyl-substituted-quinazolin-4-3h-ones-as-phosphoinositide-3-kinase-delta-pi3k%C3%AE-inhibitors
#5
Manman Wei, Xi Zhang, Xiang Wang, Zilan Song, Jian Ding, Ling-Hua Meng, Ao Zhang
PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7...
November 9, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27825552/design-synthesis-and-biological-activity-of-novel-potent-and-highly-selective-fused-pyrimidine-2-carboxamide-4-one-based-matrix-metalloproteinase-mmp-13-zinc-binding-inhibitors
#6
Hiroshi Nara, Kenjiro Sato, Akira Kaieda, Hideyuki Oki, Haruhiko Kuno, Takashi Santou, Naoyuki Kanzaki, Jun Terauchi, Osamu Uchikawa, Masakuni Kori
Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1' binder, by an appropriate linker...
September 14, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27816514/discovery-of-novel-pyrrolidineoxy-substituted-heteroaromatics-as-potent-and-selective-pi3k-delta-inhibitors-with-improved-physicochemical-properties
#7
Klemens Hoegenauer, Nicolas Soldermann, Christina Hebach, Gregory J Hollingworth, Ian Lewis, Anette von Matt, Alexander B Smith, Romain M Wolf, Rainer Wilcken, Dorothea Haasen, Christoph Burkhart, Frédéric Zécri
In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp(3) enriched derivatives retain potency and selectivity towards PI3Kδ...
October 27, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27783530/catalytic-enantioselective-synthesis-of-n-c-axially-chiral-mebroqualone-and-its-derivatives-through-reductive-asymmetric-desymmetrization
#8
Motohiro Hirai, Shumpei Terada, Hiroaki Yoshida, Kenki Ebine, Tomoaki Hirata, Osamu Kitagawa
In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)2 catalyst, treatment of various 3-(2,6-dibromophenyl)quinazolin-4-ones with NaBH4 gave optically active N-C axially chiral quinazolinone (mebroqualone) derivatives through reductive asymmetric desymmetrization (enantioselective monohydrodebromination) followed by kinetic resolution of the resulting monobromophenyl products (up to 99% ee). The enantioselectivity strongly depended on the substituent (R(2)) at the C4'position, amount of NaBH4, and reaction temperature...
October 26, 2016: Organic Letters
https://www.readbyqxmd.com/read/27782278/synthesis-of-quinazolines-from-2-aminobenzylamines-with-benzylamines-and-n-substituted-benzylamines-under-transition-metal-free-conditions
#9
Abhishek R Tiwari, Bhalchandra M Bhanage
This work reports the synthesis of quinazolines from 2-aminobenzylamines with N-substituted benzylamines in the presence of molecular iodine. The developed methodology works smoothly under transition-metal free, additive free and solvent free conditions. The use of O2 as a green oxidant makes it a greatly economical, green and sustainable protocol. Moreover, no aqueous work up is required thereby enhancing the efficiency. A series of quinazoline derivatives were synthesized successfully in good to excellent yields...
December 7, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27780761/quinazoline-derivatives-as-cathepsins-b-h-and-l-inhibitors-and-cell-proliferating-agents
#10
Neera Raghav, Suman Jangra, Ajay Kumar, Shalmoli Bhattacharyya
Cysteine Cathepsins well known to be involved in cancer, inflammation and regulation of degenerative processes like apoptosis have become specific targets in drug designing. The potential of quinazolines and their derivatives in medicinal chemistry led us to synthesise a novel series of seven compounds of quinazolines to evaluate their effect on cathepsins and cellular aspects of HepG2 cells. In the present work we report the solvent free microwave assisted synthesis of (E)-8-benzylidene-5,6,7,8-tetrahydro-2,4-diarylquinazolines as inhibitors of mammalian hepatic cysteine proteases viz...
October 22, 2016: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/27775338/ligand-optimization-by-improving-shape-complementarity-at-a-hepatitis-c-virus-rna-target
#11
Brian P Charrette, Mark A Boerneke, Thomas Hermann
Crystal structure analysis revealed key interactions of a 2-amino-benzimidazole viral translation inhibitor that captures an elongated conformation of an RNA switch target in the internal ribosome entry site (IRES) of hepatitis C virus (HCV). Here, we have designed and synthesized quinazoline derivatives with improved shape complementarity at the ligand binding site of the viral RNA target. A spiro-cyclopropyl modification aimed at filling a pocket in the back of the RNA binding site led to a fivefold increase of ligand affinity while a slightly more voluminous dimethyl substitution at the same position did not improve binding...
October 24, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27774127/discovery-of-a-series-of-5-11-dihydro-6h-benzo-e-pyrimido-5-4-b-1-4-diazepin-6-ones-as-selective-pi3k-%C3%AE-%C3%AE-inhibitors
#12
Fleur M Ferguson, Jing Ni, Tinghu Zhang, Bethany Tesar, Taebo Sim, Nam Doo Kim, Xianming Deng, Jennifer R Brown, Jean J Zhao, Nathanael S Gray
Dual inhibition of PI3K-δ and PI3K-γ is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-δ/γ selectively are chemically similar and based upon isoquinolin-1(2H)-one or quinazolin-4(3H)-one scaffolds. Here we report a chemically distinct series of potent, selective PI3K-δ/γ inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold with comparable biochemical potency and cellular effects on PI3K signaling. We envisage these molecules will provide useful leads for development of next-generation PI3K-δ/γ targeting therapeutics...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27769618/novel-substituted-hydrazono-indolo-2-1-b-quinazoline-6-12-dione-analogues-as-cytostatic-agents-synthesis-crystal-structure-biological-evaluation-and-molecular-docking-studies
#13
Ramu Guda, Sirassu Narsimha, Ramavath Babu, Srujana Muthadi, Harikiran Lingabathula, Rambabu Palabindela, Narsimha Reddy Yellu, Girijesh Kumar, Mamatha Kasula
A series of novel substituted hydrazono indolo[2,1-b]quinazoline-6,12-dione analogues have been synthesized and screened for their in vitro cytotoxic and antimicrobial activities. Among all the target compounds, 3c exhibited the most potent inhibitory activity against three cancer cell lines MCF-7, A549, HeLa with IC50 values 07.14±1.285μM, 09.18±0.968μM and 10.57±0.581μM respectively, while maintaining low toxicity towards non-cancer originated cell line, HEK-293. The detailed studies about molecular interactions with probable target protein indoleamine 2,3-dioxygenase (IDO1) were done by using docking simulations...
October 5, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27769030/differential-characterization-using-readily-accessible-nmr-experiments-of-novel-n-and-o-alkylated-quinolin-4-ol-1-5-naphthyridin-4-ol-and-quinazolin-4-ol-derivatives-with-antimycobacterial-activity
#14
Eleni Pitta, Olga Balabon, Maciej K Rogacki, Jesús Gómez, Fraser Cunningham, Jurgen Joosens, Koen Augustyns, Pieter van der Veken, Robert Bates
During the construction of bioactive molecules, regioselective alkylation of heterocyclic, N/O ambident nucleophiles is a frequently encountered synthetic transformation. In this framework, specific attention is required to unambiguously determine the structures of obtained reaction products. As part of our project on quinoloxyacetamide based antimycobacterial agents, a series of N- or O- alkylated quinolin-4-ol, 1,5-naphthyridin-4-ol and quinazolin-4-ol derivatives were prepared during the course of which we observed unexpected selectivity issues...
October 11, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27767321/phosphine-catalyzed-enantioselective-4-3-annulation-of-allenoates-with-c-n-cyclic-azomethine-imines-synthesis-of-quinazoline-based-tricyclic-heterocycles
#15
Chunhao Yuan, Leijie Zhou, Miaoren Xia, Zhanhu Sun, Dongqi Wang, Hongchao Guo
With the use of a commercially available chiral phosphine as the catalyst, the first catalytic enantioselective [4 + 3] annulation of allenoates with C,N-cyclic azomethine imines is developed. The reaction works efficiently under mild reaction conditions to afford seven-membered ring-fused quinazoline-based tricyclic heterocycles in high yields with good to excellent diastereo- and enantioselectivities.
October 21, 2016: Organic Letters
https://www.readbyqxmd.com/read/27766861/an-unusual-binding-model-of-the-methyl-9-anilinothiazolo-5-4-f-quinazoline-2-carbimidates-eht-1610-and-eht-5372-confers-high-selectivity-for-dual-specificity-tyrosine-phosphorylation-regulated-kinases
#16
Apirat Chaikuad, Julien Diharce, Martin Schröder, Alicia Foucourt, Bertrand Leblond, Anne-Sophie Casagrande, Laurent Desire, Pascal Bonnet, Stefan Knapp, Thierry Besson
Methyl 9-anilinothiazolo[5,4-f]quinazoline-2-carbimidates 1 (EHT 5372) and 2 (EHT 1610) are strong inhibitors of DYRK's family kinases. The crystal structures of the complex revealed a non-canonical binding mode of compound 1 and 2 in DYRK2 explaining the remarkable selectivity and potency of these inhibitors. The structural data and comparison presented here provide therefore a template for further improvement of this inhibitor class and for the development of novel inhibitors selectively targeting DYRK kinase...
October 21, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27763737/bifunctional-ionic-liquids-derived-from-biorenewable-sources-as-sustainable-catalysts-for-fixation-of-carbon-dioxide
#17
Vitthal B Saptal, Bhalchandra M Bhanage
A series of highly efficient, bifunctional ionic liquids containing a quaternary alkyl ammonium cation and an amine anion were prepared from choline and amino acids, respectively. Nine ILs were synthesized, characterized, and applied as organocatalysts for the chemical fixation of carbon dioxide to form cyclic carbonates and quinazoline-2,4(1 H,3 H)-diones. A binary mixture of an IL and a co-catalysts generates deep eutectic solvents (DESs) and accelerates the rate of the cycloaddition reaction at atmospheric pressure and low temperature (70 °C)...
October 20, 2016: ChemSusChem
https://www.readbyqxmd.com/read/27754446/synthesis-and-in-vitro-cytotoxic-properties-of-polycarbo-substituted-4-arylamino-quinazolines
#18
Hugues Kamdem Paumo, Tshepiso Jan Makhafola, Malose Jack Mphahlele
Herein, we describe the synthesis of novel unsymmetrical polycarbo-substituted 4-anilinoquinazolines derived from the 2-aryl-6-bromo-8-iodoquinazolines via one-pot three-step reaction sequences involving initial amination and subsequent double cross-coupling (bis-Suzuki, Sonogashira/Stille or Sonogashira/Suzuki-Miyaura) reactions with different cross coupling partners for the two carbon-carbon bond formation steps. The 4-anilinoquinazolines were evaluated for potential cytotoxicity against three cancer cell lines, namely, human breast adenocarcinoma (MCF-7) cells, human cervical cancer (HeLa) and human lung cancer (A549) cells...
October 14, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27750154/synthesis-anti-varicella-zoster-virus-and-anti-cytomegalovirus-activity-of-quinazoline-2-4-diones-containing-isoxazolidine-and-phosphonate-substructures
#19
Dorota G Piotrowska, Graciela Andrei, Dominique Schols, Robert Snoeck, Magdalena Łysakowska
Cycloadditions of N-substituted C-(diethoxyphosphoryl)nitrones to N-allylated quinazoline-2,4-diones functionalized at N3 with substituted benzoyl or benzyl groups proceeded with moderate to good diastereoselectivities (d.e. 28-68%). The synthesized isoxazolidine phosphonates were assessed for the antiviral activity against a broad range of DNA and RNA viruses. Compounds trans-13c, cis-13c/trans-13c (86:14), cis-15b/trans-15b (87:13) and trans-15d/cis-15d (95:5) exhibited the highest activity toward both TK(+) and TK(-) VZV strains (mean EC50 values in the range of 3...
October 4, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27750144/aminopurine-and-aminoquinazoline-scaffolds-for-development-of-potential-dengue-virus-inhibitors
#20
Akkaladevi Venkatesham, Milind Saudi, Suzanne Kaptein, Johan Neyts, Jef Rozenski, Mathy Froeyen, Arthur Van Aerschot
Previous efforts led to dicarboxamide derivatives like 1.3, comprising either an imidazole, pyrazine or fenyl ring as the central scaffold, with many congeners displaying strong inhibitory effects against dengue virus (DENV) in cell-based assays. Following up on some literature reports, the rationale was borne out to preserve the pending groups, now attached to either a 2,6-diaminopurine or 2,4-diaminoquinazoline scaffold. Synthetic efforts turned out less straightforward than expected, but yielded some new derivatives with low micromolar anti-DENV activity, albeit not devoid of cellular toxicity...
October 5, 2016: European Journal of Medicinal Chemistry
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