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Quinazoline

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https://www.readbyqxmd.com/read/28637410/new-research-for-quinazoline-2-4-diones-as-hppd-inhibitors-based-on-2d-mlr-and-3d-qsar-models
#1
Ying Fu, Yi-Na Sun, Hai-Feng Cao, Ke-Han Yi, Li-Xia Zhao, Jia-Zhong Li, Fei Ye
4-Hydroxyphenylpyruvate dioxygenase (HPPD), converting p-hydroxyphenylpyruvate to homogentisate, is an important target for treating type I tyrosinemia and synthesizing novel herbicides due to its significant role in tyrosine catabolism. HPPD inhibitors, sulcotrione, mesotrione and benzobicylon etc. have been used in commercialized herbicides by binding to HPPD. Based on the structure-activity relationships, a series of quinolinone-2,4-diones derivatives were studied using combined of 2D-MLR and 3D-QSARand the structural requirements for their HPPD inhibition have been investigated...
June 21, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/28628775/developing-new-pet-tracers-to-image-the-growth-hormone-secretagogue-receptor-1a-ghs-r1a
#2
Kazunori Kawamura, Masayuki Fujinaga, Yoko Shimoda, Tomoteru Yamasaki, Yiding Zhang, Akiko Hatori, Lin Xie, Hidekatsu Wakizaka, Katsushi Kumata, Takayuki Ohkubo, Yusuke Kurihara, Masanao Ogawa, Nobuki Nengaki, Ming-Rong Zhang
INTRODUCTION: `The growth hormone secretagogue receptor 1a (GHS-R1a) is the orphan G-protein-coupled receptor, and its endogenous ligand is ghrelin. GHS-R1a contributes to regulation of glucose homeostasis, memory and learning, food addiction, and neuroprotection. Several PET tracers for GHS-R1a have been developed, but none have been reported to be clinically applicable to GHS-R1a imaging. In this study, we developed three new PET tracers for GHS-R1a: (18)F-labeled 6-(4-chlorophenyl)-3-((1-(2-fluoroethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3H)-one (1), (11)C-labeled 6-(4-chlorophenyl)-3-((1-(2-methoxyethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3H)-one (2), and (11)C-labeled (S)-(4-(1H-indole-6-carbonyl)-3-methylpiperazin-1-yl)(4'-methoxy-[1,1'-biphenyl]-4-yl)methanone (3)...
June 10, 2017: Nuclear Medicine and Biology
https://www.readbyqxmd.com/read/28626532/development-of-quinazoline-pyrimidine-2-4-1h-3h-diones-as-agonists-of-cannabinoid-receptor-type-2
#3
Hai-Yan Qian, Zhi-Long Wang, You-Lu Pan, Li-Li Chen, Xin Xie, Jian-Zhong Chen
Starting from a prototypical structure 1, we describe our efforts to design and obtain novel quinazoline/pyrimidine-2,4(1H,3H)-diones with high CB2 agonist potency and selectivity as well as improved physicochemical characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for the development of future CB2 agonists.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28622906/discovery-of-novel-quinazoline-2-4-1h-3h-dione-derivatives-as-potent-parp-2-selective-inhibitors
#4
Hailong Zhao, Ming Ji, Guonan Cui, Jie Zhou, Fangfang Lai, Xiaoguang Chen, Bailing Xu
The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program...
May 26, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28615927/p-tsa-promoted-syntheses-of-5h-benzo-h-thiazolo-2-3-b-quinazoline-and-indeno-1-2-d-thiazolo-3-2-a-pyrimidine-analogs-molecular-modeling-and-in-vitro-antitumor-activity-against-hepatocellular-carcinoma
#5
Amit K Keshari, Ashok K Singh, Vinit Raj, Amit Rai, Prakruti Trivedi, Balaram Ghosh, Umesh Kumar, Atul Rawat, Dinesh Kumar, Sudipta Saha
In our efforts to address the rising incidence of hepatocellular carcinoma (HCC), we have made a commitment to the synthesis of novel molecules to combat Hep-G2 cells. A facile and highly efficient one-pot, multicomponent reaction has been successfully devised utilizing a p-toluenesulfonic acid (p-TSA)-catalyzed domino Knoevenagel/Michael/intramolecular cyclization approach for the synthesis of novel 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs bearing a bridgehead nitrogen atom...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28612027/antimicrobial-activity-of-quinazolin-derivatives-of-1-2-di-quinazolin-4-yl-diselane-against-mycobacteria
#6
Bikui Tang, Meili Wei, Qun Niu, Yinjiu Huang, Shuo Ru, Xiaofen Liu, Lin Shen, Qiang Fang
Mycobacterium tuberculosis (M. tuberculosis) is one of the leading causes of morbidity and mortality. Currently, the emergence of drug resistance has an urgent need for new drugs. In previous study, we found that 1,2-di(quinazolin-4-yl)diselane (DQYD), a quinazoline derivative, has anticancer activities against many cancers. However, whether DQYD has the activity of antimycobacterium is still little known. Here our results show that DQYD has a similar value of the minimum inhibitory concentration with clinical drugs against mycobacteria and also has the ability of bacteriostatic activity with dose-dependent and time-dependent manner...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28604871/an-extended-%C3%AF-system-and-enhanced-electronic-delocalization-on-symmetric-ru3o-ch3coo-6-l-3-n-complexes-combined-with-azanaphthalene-ligands
#7
Bruna Possato, Victor M Deflon, Zeki Naal, André L B Formiga, Sofia Nikolaou
We report on the investigation of a new series of symmetric trinuclear ruthenium complexes combined with azanaphthalene ligands: [Ru3O(CH3COO)6(L)3]PF6 where L = (1) quinazoline (qui), (2) 5-nitroisoquinoline (5-nitroiq), (3) 5-bromoisoquinoline (5-briq), (4) isoquinoline (iq), (5) 5-aminoisoquinoline (5-amiq), and (6) 5,6,7,8-tetrahydroisoquinoline (thiq). The crystal structure of complex 1, [Ru3O(CH3COO)6(qui)3]PF6, was determined by X-ray diffraction analysis, showing a high degree of co-planarity between the [Ru3O] plane and the azanaphthalene ligands...
June 12, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28549311/reaction-of-diazepam-and-related-benzodiazepines-with-chlorine-kinetics-transformation-products-and-in-silico-toxicological-assessment
#8
Inmaculada Carpinteiro, Rosario Rodil, José Benito Quintana, Rafael Cela
In this work, the reaction of four benzodiazepines (diazepam, oxazepam, nordazepam and temazepam) during water chlorination was studied by means of liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-QTOF-MS). For those compounds that showed a significant degradation, i.e. diazepam, oxazepam and nordazepam, parameters affecting to the reaction kinetics (pH, chlorine and bromide level) were studied in detail and transformation products were tentatively identified. The oxidation reactions followed pseudofirst-order kinetics with rate constants in the range of 1...
May 3, 2017: Water Research
https://www.readbyqxmd.com/read/28530833/discovery-of-small-molecules-for-repressing-cap-independent-translation-of-human-vascular-endothelial-growth-factor-hvegf-as-novel-anti-tumor-agents
#9
Shi-Ke Wang, Yue Wu, Xiao-Qin Wang, Guo-Tao Kuang, Qi Zhang, Shu-Ling Lin, Hui-Yun Liu, Jia-Heng Tan, Zhi-Shu Huang, Tian-Miao Ou
Angiogenesis is important in tumorigenesis and tumor progression. Human vascular endothelial growth factor (hVEGF) is an angiogenic growth factor that plays a crucial role in tumor progression. The G-rich region within the 5'-untranslated region (5'-UTR) of hVEGF mRNA can form a 'switchable' RNA G-quadruplex structure that is essential for a cap-independent translation initiation. We screened our small-molecule library for binders of this G-tract. One novel quinazoline derivative, compound 1, showed a significant specific interaction with the G-tract and destabilized the G-quadruplex structure...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28513683/a-theoretical-study-of-low-lying-singlet-and-triplet-excited-states-of-quinazoline-quinoxaline-and-phthalazine-insight-into-triplet-formation
#10
Mihajlo Etinski, Christel M Marian
Quinazoline, quinoxaline and phthalazine are nitrogen containing heterocyclic aromatic molecules which belong to the class diazanaphthalenes. These isomers have low-lying nπ* and naphthalene-like ππ* states that interact via spin-orbit coupling. In this contribution, we study their structure and electronic states by means of a coupled-cluster method. The computed properties are compared to those of cinnoline which were obtained in our previous study [Etinski et al., Phys. Chem. Chem. Phys., 2014, 16, 4740]...
May 31, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28501511/identification-of-quinazoline-based-inhibitors-of-irak4-for-the-treatment-of-inflammation
#11
Graham F Smith, Michael D Altman, Brian Andresen, James Baker, Jason D Brubaker, Hongmin Chen, Yiping Chen, Matthew Childers, Anthony Donofrio, Heidi Ferguson, Christian Fischer, Thierry O Fischmann, Craig Gibeau, Alexander Hicks, Sue Jin, Sam Kattar, Melanie A Kleinschek, Erica Leccese, Charles Lesburg, Chaomin Li, Jongwon Lim, Duan Liu, John K F Maclean, Faruk Mansoor, Lilly Y Moy, Erin F Mulrooney, Antoaneta S Necheva, Jeremy Presland, Larissa Rakhilina, Ruojing Yang, Luis Torres, Jie Zhang-Hoover, Alan Northrup
Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity...
June 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28499189/synthesis-biological-evaluation-and-molecular-modeling-study-of-new-1-2-4-triazole-or-1-3-4-thiadiazole-methylthio-derivatives-of-quinazolin-4-3h-one-as-dhfr-inhibitors
#12
Yomna I El-Gazzar, Hanan H Georgey, Shahenda M El-Messery, Heba A Ewida, Ghada S Hassan, Marwa M Raafat, Menna A Ewida, Hussein I El-Subbagh
A new series of 2-mercapto-quinazolin-4-one analogues was designed, synthesized and evaluated for their in vitro DHFR inhibition, antitumor and antimicrobial activity. Compound 17 proved to be the most active DHFR inhibitor with IC50 value of 0.01μM, eight fold more active than methotrexate (MTX). Compounds 16 and 24 showed antitumor activity against human Caco2 colon and MCF-7 breast tumor cell lines with IC50 values of 25.4 and 9.5μg/ml, respectively. Compounds 15, 20, 21 and 30 showed considerable activity against the Gram-positive bacteria Staphylococcus aureus while 24 and 30 proved active against Bacillus subtilis with a magnitude of potency comparable to the broad spectrum antibiotic Ciprofloxacin...
June 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28499171/quinazoline-based-%C3%AE-1-adrenoreceptor-antagonists-with-potent-antiproliferative-activity-in-human-prostate-cancer-cell-lines
#13
Valentina Maestri, Andrea Tarozzi, Elena Simoni, Antonio Cilia, Elena Poggesi, Marina Naldi, Benedetta Nicolini, Letizia Pruccoli, Michela Rosini, Anna Minarini
New α1-adrenoreceptor (α1-AR) antagonists related to prazosin and doxazosin were synthesized by replacing piperazine ring with (S)- or (R)-3-aminopiperidine. Binding studies indicated that the S configuration at the 3-C position of the piperidine ring is crucial for an optimal interaction of the compounds at all three α1-AR subtypes. Quinazolines 9 and 10, bearing a quinone ring on the lateral chain, exhibited also potent antiproliferative activity in LNCaP androgen-sensitive prostate cancer cell lines, higher than that of doxazosin...
May 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28498338/synthesis-biological-activity-and-preliminary-in-silico-admet-screening-of-polyamine-conjugates-with-bicyclic-systems
#14
Marta Szumilak, Malgorzata Galdyszynska, Kamila Dominska, Irena I Bak-Sypien, Anna Merecz-Sadowska, Andrzej Stanczak, Boleslaw T Karwowski, Agnieszka W Piastowska-Ciesielska
Polyamine conjugates with bicyclic terminal groups including quinazoline, naphthalene, quinoline, coumarine and indole have been obtained and their cytotoxic activity against PC-3, DU-145 and MCF-7 cell lines was evaluated in vitro. Their antiproliferative potential differed markedly and depended on both their chemical structure and the type of cancer cell line. Noncovalent DNA-binding properties of the most active compounds have been examined using ds-DNA thermal melting studies and topo I activity assay. The promising biological activity, DNA intercalative binding mode and favorable drug-like properties of bis(naphthalene-2-carboxamides) make them a good lead for further development of potential anticancer drugs...
May 12, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28496359/efficacy-of-cr4056-a-first-in-class-imidazoline-2-analgesic-drug-in-comparison-with-naproxen-in-two-rat-models-of-osteoarthritis
#15
Eleonora Comi, Marco Lanza, Flora Ferrari, Valeria Mauri, Gianfranco Caselli, Lucio Claudio Rovati
PURPOSE: CR4056, (2-phenyl-6-(1H-imidazol-1yl) quinazoline), an imidazoline-2 (I2) receptor ligand, is a promising analgesic drug that has been reported to be effective in several animal models of pain. The aim of this study was to evaluate the effects of CR4056 in two well-established rat models of osteoarthritis (OA), mimicking the painful and structural components of human OA. METHODS: Knee OA was induced either by single intra-articular injection of monoiodoacetate (MIA) or by medial meniscal tear (MMT) in the right knee of male rats...
2017: Journal of Pain Research
https://www.readbyqxmd.com/read/28495556/synthesis-crystal-structure-determination-biological-screening-and-docking-studies-of-n-1-substituted-derivatives-of-2-3-dihydroquinazolin-4-1h-one-as-inhibitors-of-cholinesterases
#16
Nargis Sultana, Muhammad Sarfraz, Saba Tahir Tanoli, Muhammad Safwan Akram, Abdul Sadiq, Umer Rashid, Muhammad Ilyas Tariq
Pursuing the strategy of developing potent AChE inhibitors, we attempted to carry out the N(1)-substitution of 2,3-dihydroquinazolin-4(1H)-one core. A set of 32 N-alkylated/benzylated quinazoline derivatives were synthesized, characterized and evaluated for their inhibition against cholinesterases. N-alkylation of the series of the compounds reported previously (N-unsubstituted) resulted in improved activity. All the compounds showed inhibition of both enzymes in the micromolar to submicromolar range. Structure activity relationship (SAR) of the 32 derivatives showed that N-benzylated compounds possess good activity than N-alkylated compounds...
June 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28489362/atropisomerism-and-conformational-equilibria-impact-on-pi3k%C3%AE-inhibition-of-2-6-amino-9h-purin-9-yl-methyl-5-methyl-3-o-tolyl-quinazolin-4-3h-one-ic87114-and-its-conformationally-restricted-analogs
#17
Alessio Lodola, Serena Bertolini, Matteo Biagetti, Silvia Capacchi, Fabrizio Facchinetti, Paola Maria Gallo, Alice Pappani, Marco Mor, Daniele Pala, Silvia Rivara, Filippo Visentini, Mauro Corsi, Anna Maria Capelli
IC87114 [compound 1, (2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one)] is a potent PI3K inhibitor selective for the δ isoform. As predicted by molecular modeling calculations, rotation around the bond connecting the quinazolin-4(3H)-one nucleus to the o-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the aS and aR isomers of compound 1 do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28487075/n-1h-pyrazol-3-yl-quinazolin-4-amines-as-a-novel-class-of-casein-kinase-1%C3%AE-%C3%AE%C2%B5-inhibitors-synthesis-biological-evaluation-and-molecular-modeling-studies
#18
Chandrabose Karthikeyan, Pramod Jharia, Digambar Kumar Waiker, Amy Catherine Nusbaum, Haneen Amawi, Erin Marie Kirwen, Ryann Christman, Sri Krishna Chaitanya Arudra, Laurent Meijer, Amit K Tiwari, Piyush Trivedi
Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/β, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line...
June 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28478927/discovery-of-novel-substituted-benzo-anellated-4-benzylamino-pyrrolopyrimidines-as-dual-egfr-and-vegfr2-inhibitors
#19
Tim Fischer, Thomas Krüger, Abdulkarim Najjar, Frank Totzke, Christoph Schächtele, Wolfgang Sippl, Christoph Ritter, Andreas Hilgeroth
The quinazoline scaffold is the main part of many marketed EGFR inhibitors. Resistance developments against those inhibitors enforced the search for novel structural lead compounds. We developed novel benzo-anellated 4-benzylamine pyrrolopyrimidines with varied substitution patterns at both the molecular scaffold and the attached residue in the 4-position. The structure-dependent affinities towards EGFR are discussed and first nanomolar derivatives have been identified. Docking studies were carried out for EGFR in order to explore the potential binding mode of the novel inhibitors...
June 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28476569/design-and-synthesis-of-a-fluorinated-quinazoline-based-type-ii-trk-inhibitor-as-a-scaffold-for-pet-radiotracer-development
#20
Vadim Bernard-Gauthier, Anne Mahringer, Matthew Vesnaver, Gert Fricker, Ralf Schirrmacher
NTRK1/2/3 fusions have recently been characterized as low incidence oncogenic alterations across various tumor histologies. Tyrosine kinase inhibitors (TKIs) of the tropomyosin receptor kinase family TrkA/B/C (encoded by NTRK1/2/3) are showing promises in the clinic for the treatment of cancer patients whose diseases harbor NTRK tumor drivers. We describe herein the development of [(18)F]QMICF ([(18)F]-(R)-9), a quinazoline-based type-II pan-Trk radiotracer with nanomolar potencies for TrkA/B/C (IC50=85-650nM) and relevant TrkA fusions including TrkA-TPM3 (IC50=162nM)...
June 15, 2017: Bioorganic & Medicinal Chemistry Letters
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