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Yiqiang OuYang, Wensheng Zou, Liang Peng, Zunhua Yang, Qidong Tang, Mengzi Chen, Shuang Jia, Hong Zhang, Zhou Lan, Pengwu Zheng, Wufu Zhu
Eight series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Most of the forty nine target compounds showed excellent antiproliferative activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.09 ± 0.04 μM, 1.34 ± 0.13 μM and 1.23 ± 0...
May 9, 2018: European Journal of Medicinal Chemistry
Nada A Noureldin, Hend Kothayer, El-Sayed M Lashine, Mohamed M Baraka, Yanrong Huang, Bing Li, Qinggang Ji
A series of (2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) acetamido) acids) (6 a-m), (7) has been designed to inhibit the action of fungus chitin synthase enzyme (CHS). The synthesis of the designed compounds was carried out in four steps starting from the reaction between 1-methylquinazoline-2,4(1H,3H)-dione and ethyl chloroacetate to yield the ethyl acetate derivative. This ester was hydrolyzed to the corresponding carboxylic acid derivative that was then utilized to couple several amino acids getting the final designed compounds...
May 4, 2018: European Journal of Medicinal Chemistry
Kun Hu, Qianqian Zhen, Julin Gong, Tianxing Cheng, Linjun Qi, Yinlin Shao, Jiuxi Chen
The first example of the palladium-catalyzed, three-component tandem reaction of 2-aminobenzonitriles, aldehydes, and arylboronic acids has been developed, providing a new approach for one-pot assembly of diverse quinazolines in moderate to good yields. A noteworthy feature of this method is the tolerance of bromo and iodo groups, which affords versatility for further synthetic manipulations. Preliminary mechanistic experiments indicate that this tandem process involves two possible mechanistic pathways for the formation of quinazolines via catalytic carbopalladation of the cyano group...
May 9, 2018: Organic Letters
Gagandeep Kaur, Ravi P Cholia, Gaurav Joshi, Suyog M Amrutkar, Sourav Kalra, Anil K Mantha, Uttam C Banerjee, Raj Kumar
The design and synthesis of dihydropyrazolo[1,5-c]quinazolines (1a-h) as human topoisomerase II (TopoII) catalytic inhibitors are reported. The compounds were investigated for their antiproliferative activity against the C6 rat glial cell line. Two compounds, 1b and 1h, were found to be potent cytotoxic agents against glioma cells and exerted selective TopoII inhibitory activity. Furthermore, the compounds induced alterations in reactive oxygen species levels as measured by DCFDA assay and were found to induce cell cycle arrest at the G1 phase at lower concentrations and profound apoptosis at higher concentrations...
May 8, 2018: Archiv der Pharmazie
Lu Hui, Cheng Gang, Hong Feng, Zhang Lei, Hu Youhong, Feng Linyin
The adult neurogenesis occurs throughout the life of the mammalian hippocampus and is found to be essential for learning and memory. Identifying new ways to manipulate the number of neural stem cells (NSCs) and enhance endogenous neurogenesis in adult is very important. Here we found that a novel compound, N2-(4-isopropylphenyl)-5-(3-methoxyphenoxy)quinazoline-2,4-diamine (code-named Yhhu-3792), enhanced the self-renewal capability of NSCs in vitro and in vivo. In vitro, Yhhu-3792 increased the ratio of BrdU + /DAPI+ embryonic NSCs and accelerated the growth of neurospheres significantly...
May 3, 2018: Stem Cells
John M Humphrey, Matthew Movsesian, Christopher W Am Ende, Stacey L Becker, Thomas A Chappie, Stephen Jenkinson, Jennifer L Liras, Spiros Liras, Christine C Orozco, Jayvardhan Pandit, Felix F Vajdos, Fabrice Vandeput, Eddie Yang, Frank S Menniti
We disclose the discovery and X-ray co-crystal data of potent, selective quinazoline inhibitors of PDE1. Inhibitor (S)-3 readily attains free plasma concentrations above PDE1 IC50 values and has restricted brain access. The racemic compound 3 inhibits >75% of PDE hydrolytic activity in soluble samples of human myocardium, consistent with heightened PDE1 activity in this tissue. These compounds represent promising new tools to probe the value of PDE1 inhibition in the treatment of cardiovascular disease.
May 2, 2018: Journal of Medicinal Chemistry
Bei-Ling Liao, Li Wei Pan, Yu-Jie Pan, Wei Zhang
Four natural compounds were obtained by concentrating, separating and purifying from the Folium Isatidis. These natural compounds had been characterized by elemental analysis, IR spectrum, NMR and single-crystal X-ray diffraction analysis. The results show that these natural compounds are 4(3H)-quinazolinone (I), benzoyleneurea (II), methyl 4-quinazoline-2-carboxylate (III) and ethyl 4-quinazolone-2-carboxylate (IV). The antibacterial experiment show that I and II have better activity against Staphylococcus aureus, Escherichia coli, Bacillus subtilis and Salmonella than III, IV and other multiple components...
April 25, 2018: Chemistry & Biodiversity
Xu Wang, Dandan He, Yubing Huang, Qihang Fan, Wanqing Wu, Huanfeng Jiang
A copper-catalyzed process for the synthesis of substituted quinazolines from benzonitriles and 2-ethynylanilines using molecular oxygen (O2) as sole oxidant is described. The mild catalytic system enabled the effective cleavage of the C-C triple bond and construction of new C-N, C-C bonds in one operation. Furthermore, the compound N,N-dimethyl-4-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)aniline (3dj) exhibited obvious aggregation-induced emission (AIE) phenomenon, and the fluorescence quantum yield (ΦF,film) and lifetime (τfilm) were measured to be 45...
April 24, 2018: Journal of Organic Chemistry
Jianbin Zheng, Long Chen, Owen S Skinner, Daniel Ysselstein, Jonathan Remis, Peter Lansbury, Renato Skerlj, Michael Mrosek, Ursula Heunisch, Stephan Krapp, Joel Charrow, Michael Schwake, Neil L Kelleher, Richard B Silverman, Dimitri Krainc
β-Glucocerebrosidase (GCase) mutations cause Gaucher's disease and are a high risk factor in Parkinson's disease. The implementation of a small molecule modulator is a strategy to restore proper folding and lysosome delivery of degradation-prone mutant GCase. Here, we present a potent quinazoline modulator, JZ-4109, which stabilizes wild-type and N370S mutant GCase and increases GCase abundance in patient-derived fibroblast cells. We then developed a covalent modification strategy using a lysine targeted inactivator (JZ-5029) for in vitro mechanistic studies...
April 20, 2018: Journal of the American Chemical Society
Briohny H Spencer, Catherine M McDermott, Russ Chess-Williams, David Christie, Shailendra Anoopkumar-Dukie
BACKGROUND/AIMS: Docetaxel is currently the first-line chemotherapeutic agent available for the treatment of patients with advanced prostate cancer (PCa). While docetaxel has been shown to modestly improve survival times for patients; they also experience significant docetaxel-induced toxicities. If treatment failure occurs, there are currently limited alternatives that show survival benefits for patients and therefore there is an urgent need for adjunct therapies. Some quinazoline-based alpha1-adrenoceptor (ADR) antagonists have previously been shown to have cytotoxic actions in PCa cells, but there is no research into their effects on docetaxel-induced toxicity...
April 17, 2018: Pharmacology
Doan Thanh Hieu, Duong Tien Anh, Hai Pham-The, Le-Thi-Thu Huong, Eun Jae Park, Jeong Eun Choi, Jong Soon Kang, Sang-Bae Han, Phan Thi Phuong Dung, Nguyen-Hai Nam
In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N-hydroxybenzamides incorporating quinazoline heterocycles (4a-i, 6a-i). Bioevaluation showed that these quinazoline-based hydroxamic acids and N-hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). In term of cytotoxicity, several compounds, e.g. 4g, 4c, 4g-i, 6c, and 6h, displayed from 5- up to 10-fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat)...
April 18, 2018: Chemistry & Biodiversity
Prateek Pathak, Parjanya Kumar Shukla, Vikas Kumar, Ankit Kumar, Amita Verma
A series of quinazoline clubbed 1,3,5-triazine derivatives (QCT) were synthesized and evaluated for their in vitro anticancer activity against HeLa (human cervical cancer), MCF-7 (human breast cancer cell), HL-60 (human promyelocytic leukemia cell), HepG2 (human Hepatocellular carcinoma cell), and one normal cell line HFF (human foreskin fibroblasts). In vitro assay result encouraged to further move towards in ovo anticancer evaluation using chick embryo. The series of QCT derivatives showed higher anticancer and antiangiogenic activity against HeLa and MCF-7 cell lines...
April 16, 2018: Inflammopharmacology
V Alagarsamy, K Chitra, G Saravanan, V Raja Solomon, M T Sulthana, B Narendhar
Most of the drugs and pharmacologically relevant molecules possess heterocyclic ring structures and presence of hetero atoms or groupings divulges privileged specificities in their pharmacological targets. Especially the heterocyclic systems, quinazoline is a biologically imperative scaffold known to be linked with several pharmacological activities. Some of the protuberant pharmacological responses attributed to this system are analgesic, anti-inflammatory, anti-convulsant, sedative-hypnotic, anti-histaminic, anti-hypertensive, anti-cancer, anti-microbial, anti-tubercular and anti-viral activities...
May 10, 2018: European Journal of Medicinal Chemistry
Monika Kubacka, Magdalena Kotańska, Grzegorz Kazek, Anna Maria Waszkielewicz, Henryk Marona, Barbara Filipek, Szczepan Mogilski
The aim of this study was to explore the α1 -adrenoceptor-independent mechanisms involved in the vasorelaxant properties of two non-quinazoline α1 -adrenoceptors antagonists (MH-76 and MH-79). Endothelium intact and endothelium denuded rat aorta was contracted with 1 μM phenylephrine to plateau, and the vasodilatory effect of MH-76 and MH-79 was examined in the absence or presence of inhibitors of the different signal transduction pathways. cGMP concetration was measured in rat aorta (enzyme immunoassay kit)...
April 10, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Tanmay Chatterjee, Dong In Kim, Eun Jin Cho
A transition-metal free procedure for the synthesis of a highly valuable class of heteroaromatics, quinazolines, was developed by using easily available 2-aminobenzylamines and α,α,α-trihalotoluenes. The transformation proceeded smoothly in the presence of only sodium hydroxide and molecular oxygen in water at 100 °C, furnishing a variety of 2-aryl quinazolines. The crystallization process of the crude reaction mixture for the purification of the solid products circumvents huge solvent consuming work-up and column chromatographic techniques, which make the overall process more sustainable and economical...
April 12, 2018: Journal of Organic Chemistry
Sofia Almeida, Roger Marti, Ennio Vanoli, Stefan Abele, Simone Tortoioli
A novel and convenient one-pot sequential cascade method for the preparation of 2-trifluoromethylquinazolin-4(3 H)-ones is described. Trifluoroacetic acid (TFA) was employed as inexpensive and readily available CF3 source, which in the presence of T3P was condensed with a variety of anthranilic acids and amines to provide the products in up to 75% yield. The protocol was proved to be robust on 80 g scale, and the synthetic versatility of the prepared quinazolinon-4-ones was demonstrated by derivatization to further useful building blocks...
April 12, 2018: Journal of Organic Chemistry
Jie Zhou, Ming Ji, Haiping Yao, Ran Cao, Hailong Zhao, Xiaoyu Wang, Xiaoguang Chen, Bailing Xu
Novel quinazoline-2,4(1H,3H)-dione derivatives bearing a 3-amino pyrrolidine moiety were designed and synthesized as PARP-1/2 inhibitors. Structure-activity relationships were examined which revealed a number of potent PARP-1/2 inhibitors with moderate selectivity toward PARP-1 over PARP-2. These compounds had IC50 values against PARP-1 at the 10-9 M level and against PARP-2 at the 10-8 M level. Among all the synthesized compounds, compounds 10 and 11 displayed strong cytotoxicities which are either used as a single agent or in combination with temozolomide (TMZ) in MX-1 cells (10, IC50 < 3...
April 12, 2018: Organic & Biomolecular Chemistry
Rashmi Prakash, Bidisha R Bora, Romesh C Boruah, Sanjib Gogoi
An unprecedented Ru(II)-catalyzed C-H activation and annulation reaction, which proceeds via C-C triple bond cleavage, is reported. This reaction of 2-phenyldihydrophthalazinediones with alkynes, which works most efficiently in the presence of bidented ligand 1,3-bis(diphenylphosphino)propane, affords good yields of substituted quinazolines.
April 6, 2018: Organic Letters
Xiaowei Zhang, Sheng Wang, Yu Liu, Chanjuan Xi
A triflate-triggered intermolecular cyclization of carbodiimides to provide 2-amino-4-imino-quinazolines, which could be easily transformed to 2-aminoquinazolinones and 2,4-diaminoquinazolines in high yield, has been reported. A variety of functional groups are tolerated in the 2-amino-4-iminoquinazoline scaffolds.
April 5, 2018: Organic Letters
Linkui Zhang, Ying Zhao, Jian Wang, Donglin Yang, Chenwen Zhao, Changli Wang, Chao Ma, Maosheng Cheng
Diverse of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed, synthesized and evaluated for their neuroprotective activity against NMDA-induced cytotoxicity in vitro, and 5q exhibited excellent neuroprotective activity. The compound 5q was selected for further investigation. We found that 5q could attenuate Ca2+ influx induced by NMDA, meanwhile, 5q could suppress the NR2B up-regulation and increase p-ERK1/2 expression. The molecular docking results showed that 5q might fit well in the binding pocket of 4 and interact with some key residues in the binding pocket of 1 simultaneously...
March 23, 2018: European Journal of Medicinal Chemistry
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