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Oleksandra Kolomoets, Оleksii Voskoboynik, Oleksii Antypenko, Galyna Berest, Inna Nosulenko, Vitaliy Palchikov, Olexandr Karpenko, Sergiy Kovalenko
Present work is devoted to the purposeful search of novel promising anti-inflammatory agents among the insufficiently known 3'-R-10'-R1-spiro[hetaryl-3(4),6'-[1,2,4]triazino[2,3-c]quinazolin]-2'(7'H)-ones. The virtual combinatorial library of previously unknown spiro-condensed derivatives of [1,2,4]triazino[2,3-c]quinazolines was formed and promising COX-2 inhibitors were identified by molecular docking method. Potential anti-inflammatory agents were synthesized by [5+1]-cyclocondensation of substituted 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-ones with heterocyclic ketones...
December 2017: Acta Chimica Slovenica
Tapan Dey, Prachurjya Dutta, Prasenjit Manna, Jatin Kalita, Hari Prasanna Deka Boruah, Alak Kumar Buragohain, Balagopalan Unni
Vasicinone, a quinazoline alkaloid from Adhatoda vasica Nees. is well known for its bronchodilator activity. However its anti-proliferative activities is yet to be elucidated. Here-in we investigated the anti-proliferative effect of vasicinone and its underlying mechanism against A549 lung carcinoma cells. The A549 cells upon treatment with various doses of vasicinone (10, 30, 50, 70 μM) for 72 h showed significant decrease in cell viability. Vasicinone treatment also showed DNA fragmentation, LDH leakage, and disruption of mitochondrial potential, and lower wound healing ability in A549 cells...
January 9, 2018: Biomolecules & Therapeutics
Shaofeng Sun, Jingwen Zhang, Ningning Wang, Xiangkai Kong, Fenghua Fu, Hongbo Wang, Jianwen Yao
Both EGFR and VEGFR-2 play a critical role in tumor growth, angiogenesis and metastasis, and targeting EGFR and VEGFR-2 simultaneously represents a promising approach to cancer treatment. In this work, a series of novel quinazoline- and thiourea-containing sorafenib analogs (10a-v) were designed and synthesized as EGFR and VEGFR-2 dual TK inhibitors. Their in vitro enzymatic inhibitory activities against EGFR and VEGFR-2, and antiproliferative activities against HCT-116, MCF-7 and B16 cell lines were evaluated and described...
December 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Lin Zhang, Yuanyuan Shan, Xingyue Ji, Mengyuan Zhu, Chuansheng Li, Ying Sun, Ru Si, Xiaoyan Pan, Jinfeng Wang, Weina Ma, Bingling Dai, Binghe Wang, Jie Zhang
Receptor tyrosine kinases (RTKs), especially VEGFR-2, TIE-2, and EphB4, play a crucial role in both angiogenesis and tumorigenesis. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat such pathological traits with single-target agents. Herein, we developed two classes of multi-target RTK inhibitors (RTKIs) based on the highly conserved ATP-binding pocket of VEGFR-2/TIE-2/EphB4, using previously reported BPS-7 as a lead compound. These multi-target RTKIs exhibited considerable potential as novel anti-angiogenic and anticancer agents...
December 1, 2017: Oncotarget
Andrii Monastyrskyi, Simon Bayle, Victor Quereda, Wayne Grant, Michael Cameron, Derek Duckett, William Roush
The development of a new series of apoptosis signal-regulating kinase 1 (ASK1) inhibitors is described. Starting from purine, pyrimidine and quinazoline scaffolds identified by high throughput screening, we used tools of structure-based drug design to develop a series of potent kinase inhibitors, including 2-arylquinazoline derivatives 12 and 23, with submicromolar inhibitory activities against ASK1. Kinetic analysis demonstrated that the 2-arylquinazoline scaffold ASK1 inhibitors described herein are ATP competitive...
December 13, 2017: Bioorganic & Medicinal Chemistry Letters
Sheng-Ge Li, Kai-Bo Wang, Chi Gong, Yu Bao, Ning-Bo Qin, Da-Hong Li, Zhan-Lin Li, Jiao Bai, Hui-Ming Hua
Seventeen quinazoline alkaloids and derivatives, containing two pairs of new epimers, named as (S)- and (R)-1-(2-aminobenzyl)-3-hydroxypyrrolidin-2-one β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (1, 2), (S)- and (R)-vasicinone β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (3, 4), and a new enantiomer (12b), together with six known ones (5-8, 10, and 12a), and three pairs of known enantiomers (9, 11, and 13), were isolated from the ethanol extracts of the seeds of Peganum harmala L.. Their structures including the absolute configuration were elucidated by using 1D and 2D NMR, and ECD calculation approaches...
December 5, 2017: Bioorganic & Medicinal Chemistry Letters
V Sridhar, S K Arepalli, L R Velatooru, J Venkateswara Rao, P Kavin Kennedy, B Narsaiah
Several quinazoline derivatives have been found to possess a broad spectrum of biological activities. Previously our research group has synthesized and studied the anti-proliferative effects of N-Decyl-N-(2-Methyl-4-Quinazolinyl) Amine (DMQA). The current study evaluated the cytotoxic and apoptotic properties of DMQA in THP-1 cells. The cytotoxic potential of DMQA was assessed using MTT assay on a panel of cancer cell lines which include HeLa, Mia PaCa-2, A 375, B16-F10, A 549,A 431, U937, THP-1, HL-60 and peripheral blood mononuclear cells (PBMC's)...
December 7, 2017: Chemico-biological Interactions
Doan Thanh Hieu, Duong Tien Anh, Nguyen Minh Tuan, Pham-The Hai, Le-Thi-Thu Huong, Jisung Kim, Jong Soon Kang, Tran Khac Vu, Phan Thi Phuong Dung, Sang-Bae Han, Nguyen-Hai Nam, Nguyen-Dang Hoa
In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized several series of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones (4a-h, 8a-d, 10a-d). Biological evaluation showed that these hydroxamic acids were generally cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). It was found that the N-hydroxypropenamides (10a-d) were the most potent, both in term of HDAC inhibition and cytotoxicity...
December 5, 2017: Bioorganic Chemistry
Rezvan Rezaee Nasab, Farshid Hassanzadeh, Ghadam Ali Khodarahmi, Mahmoud Mirzaei, Mahboubeh Rostami, Ali Jahanian-Najaf Abadi
A series of novel derivatives of quinazolinone Schiff bases were synthesized from benzoic acid starting material and evaluated for potential cytotoxic activities against the human breast adenocarcinoma (MCF-7) and the human colon adenocarcinoma (HT-29) cell lines. Compared to the reference drug, these compounds showed good cytotoxic activities against studied cell lines especially compounds 4d and 4e. The ground-state geometries of these compounds (4a-g) were optimized at the B3LYP/6-31G* density functional theory (DFT) level...
December 2017: Research in Pharmaceutical Sciences
Chenzhou Hao, Fan Zhao, Hong Yan Song, Jing Guo, Xiaodong Li, Xiaolin Jiang, Ran Huan, Shuai Song, Qiaoling Zhang, Ruifeng Wang, Kai Wang, Yu Pang, Tongchao Liu, Tianqi Lu, Wanxu Huang, Jian Wang, Bin Lin, Zhonggui He, Haitao Li, Feng Li, Dongmei Zhao, Maosheng Cheng
Herein, we report the discovery and characterization of a novel class of PAK4 inhibitors with a quinazoline scaffold. Based on the shape and chemical composition of the ATP-binding pocket of PAKs, we chose a 2, 4-diaminoquinazoline series of inhibitors as a starting point. Guided by X-ray crystallography and a structure-based drug design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors' selectivity, therapeutic potency, and pharmaceutical properties were optimized...
November 30, 2017: Journal of Medicinal Chemistry
Chao Yu, Xuefeng Guo, Mengqi Shen, Bo Shen, Michelle Muzzio, Zhouyang Yin, Qing Li, Zheng Xi, Junrui Li, Christopher Takakazu Seto, Shouheng Sun
We report a facile interface assembly method to assemble a monolayer array of nitrogen-doped graphene (NG) and nanoparticles (NPs) and then to transfer the dual monolayers onto a solid substrate. Using 3 nm NiPd NPs as an example, we demonstrate that NiPd-NG-Si can function as a catalyst probe and show maximum NiPd catalysis for the hydrolysis of ammonia borane (H3NBH3, AB) with its TOF = 4896.8 h-1 and Ea = 18.8 kJ/mol. The NiPd-NG-Si is also highly active for catalyzing the synthesis of quinazolines in water, only 0...
November 22, 2017: Angewandte Chemie
Hatem A Abuelizz, Mohamed Marzouk, Hazem Ghabbour, Rashad Al-Salahi
In this study, a new series of quinazoline derivatives (3-26) was synthesized and characterized via physicochemical and spectral means. Treatment of 2-amino-5-methylbenzoic acid with butyl isothiocyanate resulted in the new 2-thioxoquinazolin-4-one (3). Alkylation and hydrazinolysis of the inherent thioxo group in (1-3) afforded the corresponding thioethers (4-23) and hydrazine derivatives (24 and 25), then 24 was further transformed into tricyclic derivative 26 via cyclocondensation reaction. Compounds 1 and 2, which were previously synthesized, were found to exhibit anticancer activity...
November 2017: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
Nawid Madjroh, Emma Rie Olander, Christoffer Bundgaard, Pella Cecilia Söderhielm, Anders A Jensen
The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator (PAM) at GABAA receptors (GABAARs) (Hammer et al., 2015). In the present study, we have identified a novel methaqualone analog, 2-phenyl-3-(p-tolyl)quinazolin-4(3H)-one (PPTQ), in a screening of 67 analogs at five αβ2γ2S GABAAR subtypes and delineated its functional properties and mechanism of action at wild-type and mutant GABAARs expressed in Xenopus laevis oocytes by two-electrode voltage clamp electrophysiology...
January 2018: Biochemical Pharmacology
Takehiko Iwaki, Taisaku Tanaka, Kazuo Miyazaki, Yamato Suzuki, Yoshihiko Okamura, Akira Yamaki, Makoto Iwanami, Naomi Morozumi, Mayumi Furuya, Yoshiaki Oyama
Natriuretic peptide receptor A (NPR-A) agonists were evaluated in vivo by optimizing the structure of quinazoline derivatives to improve agonistic activity for rat NPR-A. A 1,4-Cis-aminocyclohexylurea moiety at 4-position and hydroxy group of d-alaninol at 2-position on the quinazoline ring were found to be important factors in improving rat NPR-A activity. We identified potent quinazoline and pyrido[2,3-d]pyrimidine derivatives against rat NPR-A, with double-digit nanomolar EC50 values. The in vivo results showed that compound 56b administered at 1...
November 6, 2017: Bioorganic & Medicinal Chemistry
Yicong Chen, Leo Veenman, Sukhdev Singh, Fubing Ouyang, Jiahui Liang, Weixian Huang, Ilan Marek, Jinsheng Zeng, Moshe Gavish
BACKGROUND AND PURPOSE: Focal cortical infarction causes neuronal apoptosis in the ipsilateral nonischemic thalamus and hippocampus, which is potentially associated with poststroke cognitive deficits. TSPO (translocator protein) is critical in regulating mitochondrial apoptosis pathways. We examined the effects of the novel TSPO ligand 2-(2-chlorophenyl) quinazolin-4-yl dimethylcarbamate (2-Cl-MGV-1) on poststroke cognitive deficits, neuronal mitochondrial apoptosis, and secondary damage in the ipsilateral thalamus and hippocampus after cortical infarction...
December 2017: Stroke; a Journal of Cerebral Circulation
Xueqing Li, Rutao Wang, Yang Liu, Yun Liu, Heng Zheng, Yabo Feng, Na Zhao, Hongbin Geng, Wanzhi Zhang, Aidong Wen
BACKGROUND: Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters...
November 16, 2017: BMC Pharmacology & Toxicology
Rashad Al-Salahi, El-Hassane Anouar, Mohamed Marzouk, Hanan Aa Taie, Hatem A Abuelizz
AIM: The present study was carried out to assess a new series of triazoloquinazolines 1-40 for their antioxidant activities using 1,1-diphenyl-2-picryl hydrazyl radical scavenging, ferric reduction antioxidant power and reducing power capability assays. RESULTS: All triazoloquinazolines 1-40 exhibited antioxidant activity ranged from weak to moderate and high. The obtained findings revealed that the triazoloquinazolines 30, 36 and 38-40 have superiority among all compounds, demonstrating the highest capacity to deplete 1,1-diphenyl-2-picryl hydrazyl and free radicals, in relation to butylated hydroxyl toluene, as a synthetic antioxidant agent...
November 17, 2017: Future Medicinal Chemistry
Beatrice Castellani, Eleonora Diamanti, Daniela Pizzirani, Piero Tardia, Martina Maccesi, Natalia Realini, Paola Magotti, Gianpiero Garau, Thomas Bakkum, Silvia Rivara, Marco Mor, Daniele Piomelli
N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is a membrane-associated zinc enzyme that catalyzes the hydrolysis of N-acylphosphatidylethanolamines (NAPEs) into fatty acid ethanolamides (FAEs). Here, we describe the identification of the first small-molecule NAPE-PLD inhibitor, the quinazoline sulfonamide derivative 2,4-dioxo-N-[4-(4-pyridyl)phenyl]-1H-quinazoline-6-sulfonamide, ARN19874.
November 16, 2017: Chemical Communications: Chem Comm
Tarosh S Patel, Jaimin D Bhatt, Satish F Vanparia, Urmila H Patel, Ritu B Dixit, Chaitanya J Chudasama, Bhavesh D Patel, Bharat C Dixit
Grimmel's method was optimized as well as modified leading to the cyclization and incorporation of alanine linked sulphonamide in 4-quinazolin-(3H)-ones. Further, the generation of heterocyclic motif at position-3 of 4-quinazolinones was explored by synthesis of imines, which unfortunately led to an isomeric mixture of stereoisomers. The hurdle of diastereomers encountered on the path was eminently rectified by development of new rapid and reproducible methodology involving the use of imidazolium based ionic liquid as solvents as well as catalyst for cyclization as well as synthesis of imines in situ at position-3 leading to procurement of single E-isomer as the target hybrid heterocyclic molecules...
October 31, 2017: Bioorganic & Medicinal Chemistry
Gabriella Guerrini, Giovanna Ciciani, Letizia Crocetti, Simona Daniele, Carla Ghelardini, Maria Paola Giovannoni, Antonella Iacovone, Lorenzo Di Cesare Mannelli, Claudia Martini, Claudia Vergelli
Compounds that can act on GABAA receptor subtype in a selective manner, without the side effects of classical benzodiazepine ligands, represent promising therapeutic tools in neurological disorder as well as for relief of pain or in comorbidity of anxiety states and depression. Continuing our research on GABAA receptor subtype ligands, here is reported the synthesis of a series of pyrazolo[1,5-a]quinazoline 3- and/or 8-substituted as 5-deaza analogues of previous reported pyrazolo[5,1-c][1,2,4]benzotriazine, already identified as selective GABAA receptor subtype ligands endowed with anxiolytic-like and antihyperalgesic action or enhancer cognition...
November 22, 2017: Journal of Medicinal Chemistry
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