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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 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 10, 2017: Journal of Medicinal Chemistry
Sethuraman Muthuramalingam, Themmila Khamrang, Marappan Velusamy, Ramasamy Mayilmurugan
New copper(ii) complexes, [Cu(L1)2(H2O)](ClO4)2, 1 [L1 = 2-pyridin-2-yl-quinoline], [Cu(L2)2(H2O)](ClO4)2, 2 [L2 = 2-pyridin-2-yl-quinoxaline], [Cu(L3)2(H2O)](ClO4)2, 3 [L3 = 6,7-dimethyl-2-pyridin-2-yl-quinoxaline], [Cu(L4)2(H2O)](ClO4)2, 4 [L4 = 4-phenyl-2-pyridin-2-yl-quinoline] and [Cu(L5)2(H2O)](ClO4)2, 5 [L5 = 4-phenyl-2-pyridin-2-yl-quinazoline], were synthesized and characterized as catalysts for selective fixation of atmospheric CO2. The molecular structure of 2 was determined by single-crystal X-ray studies and shown to have an unusual trigonal bipyramid geometry (τ, 0...
November 9, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
Lan Yang, Shijia Ge, Jian Huang, Xiaoping Bao
A series of novel (E)-2-(4-(1H-1,2,4-triazol-1-yl)styryl)-4-(alkyl/arylmethyleneoxy)quinazoline derivatives (4a-4s) were synthesized in good to excellent yields, and their structures were fully characterized by [Formula: see text] NMR, [Formula: see text] NMR, HRMS and IR spectra. The structure of compound 4b was further confirmed via single-crystal X-ray diffraction analysis. The bioassay results indicated that compounds 4s, 4q and 4n inhibit phytopathogenic bacterium Xanthomonas axonopodis pv. citri (Xac) more potently than commercial bactericide bismerthiazol...
November 8, 2017: Molecular Diversity
Zheng Cao, Shahriar Koochekpour, Stephen E Strup, Natasha Kyprianou
Dysregulation of transforming growth factor-β1 (TGF-β1) and insulin-like growth factor (IGF) axis has been linked to reactive stroma dynamics in prostate cancer progression. IGF binding protein-3 (IGFBP3) induction is initiated by stroma remodeling and could represent a potential therapeutic target for prostate cancer. In previous studies a lead quinazoline-based Doxazosin® derivative, DZ-50, impaired prostate tumor growth by targeting proteins involved in focal adhesion, anoikis resistance and epithelial-mesenchymal-transition (EMT)...
October 3, 2017: Oncotarget
Mostafa M Ghorab, Mansour S Alsaid, Aiten M Soliman, Abdullah A Al-Mishari
Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5-19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5-19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Tim Fischer, Karim Najjar, Frank Totzke, Christoph Schächtele, Wolfgang Sippl, Christoph Ritter, Andreas Hilgeroth
With ongoing resistance problems against the marketed EGFR inhibitors having a quinazoline core scaffold there is a need for the development of novel inhibitors having a modified scaffold and, thus, expected lower EGFR resistance problems. An additional problem concerning EGFR inhibitor resistance is an observed heterodimerization of EGFR with PDGFR-β that neutralises the sole inhibitor activity towards EGFR. We developed novel pyrimido[4,5-b]indoles with varied substitution patterns at the 4-anilino residue to evaluate their EGFR and PDGFR-β inhibiting properties...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Rasha M Aly, Rabah A T Serya, Amira M El-Motwally, Ahmed Esmat, Safinaz Abbas, Dalal A Abou El Ella
EGFR has a key role in cell growth. Its mutation and overexpression share in epithelial malignancies and tumor growth. Quinazoline and quinoline derivatives are common anticancer intracellular inhibitors of EGFR kinase, and their optimization is an important issue for development of potent targeted anticancer agents. Based on these facts, different strategies were used for optimizing our reported quinoline-3-carboxamide compound III (EGFR IC50 = 5.283 µM and MCF-7 IC50 = 3.46 µM) through different molecular modeling techniques...
October 30, 2017: Bioorganic Chemistry
Md Maqusood Alam, Ahmed H E Hassan, Yeong Ho Kwon, Hyo Jong Lee, Nam Yong Kim, Kyung Hoon Min, Sang-Yoon Lee, Dong-Hyun Kim, Yong Sup Lee
The evolving resistance to the currently used chemotherapeutic agents requires continuous efforts to develop new anticancer agents overcoming resistance and with lower side effects. Polypharmacology via designing a single molecule intercepting multiple signaling pathways is more effective than targeting a single one. Several alkylphosphocholines show anticancer activity via inhibition of Akt phosphorylation. On the other hand, several molecules having quinazoline scaffold elicit anticancer activity through inhibition of epidermal growth factor receptor (EGFR) tyrosine kinases...
November 1, 2017: Archives of Pharmacal Research
Rajitha Bollu, Saleha Banu, Suresh Kasaboina, Rajashaker Bantu, Lingaiah Nagarapu, Sowjanya Polepalli, Nishant Jain
A novel synthetic protocol has been developed for the synthesis of 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids 7a-n by employing Pd-catalyzed CH arylation in presence of 5-10% phosphine ligand in good to excellent yields and evaluated for their anti-proliferative activity against three cancer cell lines such as A549 (lung), HeLa (cervical), MDA-MB-231 (breast). Compounds 7d, 7f, 7l and 7n exhibited promising anti-proliferative activity with GI50 values ranging from 0.37 to 2.73 µM respectively against A549, HeLa, and MDA-MB-231, while compound 7f showed significant activity against MDA-MB-231 with GI50 value 0...
October 20, 2017: Bioorganic & Medicinal Chemistry Letters
Amit K Keshari, Ashok K Singh, Umesh Kumar, Vinit Raj, Amit Rai, Pranesh Kumar, Dinesh Kumar, Biswanath Maity, Sneha Nath, Anand Prakash, Sudipta Saha
5H-benzo[h]thiazolo[2,3-b]quinazoline scaffold is known to have an antitumor effect on certain types of malignancies; however, its effect on hepatocellular carcinoma (HCC) remains unclear. Previously, we reported p-toluenesulfonic acid-promoted syntheses, molecular modeling and in vitro antitumor activity of 5H-benzo[h]thiazolo[2,3-b]quinazoline against human hepatoma (Hep-G2) cells where compounds 4A and 6A were found to be potent inhibitors among the series. In continuation to our previous effort to develop novel therapeutic strategies for HCC treatment, here we investigated the in vivo antitumor activity and the mechanism underlying the effects of 4A and 6A in N-nitrosodiethylamine (NDEA)-induced HCC using male Wistar rats...
2017: Drug Design, Development and Therapy
Malose J Mphahlele, Samantha Gildenhuys, Nishal Parbhoo
In this paper, we describe the synthesis of the 5-styryltetrazolo[1,5-c]quinazolines substituted at the 9-position with a 4-fluorophenyl ring directly or via a conjugated π-spacer (C=C or C≡C bond) based on the 6-bromo-4-chloro-2-styrylquinazoline scaffold. The structures of the synthesized compounds were characterized based on a combination of ¹H-NMR, (13)C-NMR, IR and high resolution mass spectral data as well as microanalyses. The tetrazoloquinazolines were evaluated for potential in vitro cytotoxicity against the human breast adenocarcinoma (MCF-7) and cervical cancer (HeLa) cells...
October 26, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Hua-Bo Han, Rong-Zhen Cui, Guang-Zhao Lu, Zheng-Guang Wu, You-Xuan Zheng, Liang Zhou, Hongjie Zhang
Two novel iridium(iii) complexes, Ir(tfmpiq)2(acac) (tfmpiq = 1-(2,6-bis(trifluoromethyl)pyridin-4-yl)isoquinoline, acac = acetylacetone) and Ir(tfmpqz)2(acac) (tfmpqz = 4-(2,6-bis(trifluoromethyl)pyridin-4-yl)quinazoline), were synthesized and thoroughly investigated. Both complexes emit orange-red photoluminescence with high quantum yields (Ir(tfmpiq)2(acac): λmax: 587 nm, ηPL: 42%; Ir(tfmpqz)2(acac): λmax: 588 nm, ηPL: 91%). Furthermore, the complex containing quinazoline shows higher electron mobility than that with isoquinoline...
November 7, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
Mansour S Alsaid, Abdullah A Al-Mishari, Aiten M Soliman, Fatma A Ragab, Mostafa M Ghorab
An array of some new N-(substituted)-2-((4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)acetamide 5-19 were synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl)benzenesulfonamide 4, to be assessed for their cytotoxic activity against A549 lung cancer cell line and to determine their inhibitory effect on EGFR tyrosine kinase enzyme. Compounds 5-19 showed high activity towards A549 cell line with IC50 values of 0.12-8.70 μM. Compounds 6, 12 and 18 were the most potent in this series...
December 1, 2017: European Journal of Medicinal Chemistry
Mani Ramanathan, Yi-Hung Liu, Shie-Ming Peng, Shiuh-Tzung Liu
A transition metal-free synthesis of multisubstituted quinazolin-4(3H)-imines has been realized by the direct reaction of aryldiazonium salts, nitriles, and 2-cyanoanilines in a one-pot fashion. This strategy utilizes the in situ formation of reactive N-arylnitrilium intermediate, which undergoes further tandem cyclization with consecutive formation of N-C bonds. Broad functional group compatibility, mild conditions, shorter time, and operational simplicity are the notable features of this report.
October 13, 2017: Organic Letters
Chungang Gu, Shenghua Wen, Peter Doig, Eric Gangl, Xiaolan Zheng, Yanjun Wang, Jeffrey W Johannes
Phosphorylation of xenobiotics is rare, probably due to a strong evolutionary pressure against it. This rarity may have attracted more attention recently, owing to intentionally designed kinase-substrate analogs which depend on kinase-catalyzed activation to form phosphorylated active drugs. We report a rare phosphorylated metabolite observed unexpectedly in mouse plasma samples after an oral dose of a Tankyrase inhibitor that was not intended to be a kinase substrate, i.e. (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (AZ2381)...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Amit N Pandya, Eric M Villa, E Jeffrey North
A simple and efficient approach for the synthesis of 2-aminoquinazoline derivatives in moderate to good yields. This reaction employs mild reaction conditions, is metal-free and utilizes readily available starting materials making it a more viable reaction for the scale up synthesis and ligand diversity. Notably, this methodology allows the synthesis of 2-aminoquinazolines using a free amine or cyclic amine enabling structural diversity and good atom economy.
March 29, 2017: Tetrahedron Letters
Takehiko Iwaki, Yuji Nakamura, Taisaku Tanaka, Yasuyuki Ogawa, Osamu Iwamoto, Yoshihiko Okamura, Yumi Kawase, Mayumi Furuya, Yoshiaki Oyama, Takahiro Nagayama
Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48, which showed potent agonistic activity for NPR-A with an EC50 value of 0.073μM, indicating 350-fold potency compared to the hit compound 3...
September 18, 2017: Bioorganic & Medicinal Chemistry Letters
Liuchang Wang, Pengna Li, Baolin Li, Yawen Wang, Jiangtao Li, Limei Song
In an attempt to explore a new class of epidermal growth factor receptor (EGFR) inhibitors, novel 4-stilbenylamino quinazoline derivatives were synthesized through a Dimorth rearrangement reaction and characterized via IR, ¹H-NMR, (13)C-NMR, and HRMS. Methoxyl, methyl, halogen, and trifluoromethyl groups on stilbeneamino were detected. These synthesized compounds were evaluated for antitumor activity in vitro against eight human tumor cell lines with an MTS assay. Most synthesized compounds exhibited more potent activity (IC50 = ~2...
September 28, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
(no author information available yet)
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis...
December 2016: Molecular Oncology
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