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Minhang Xin, Weiming Duan, Yifan Feng, Yuan-Yuan Hei, Hao Zhang, Ying Shen, Hong-Yi Zhao, Shuai Mao, San-Qi Zhang
Phosphoinositide 3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ was confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Herein, we reported a novel series of 4-pyrrolidineoxy or 4-piperidineamino substituted quinazolines, showing potent PI3Kδ inhibitory activities. Among these compounds, 12d, 14b and 14c demonstrated higher potency against PI3Kδ with the half maximal inhibitory concentration (IC50 ) values of 4.5, 3.0, and 3...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Weijie Hou, Yan Ren, Zhenhua Zhang, Huan Sun, Yongfen Ma, Bo Yan
A series of novel quinazoline derivatives bearing various C-6 benzamide substituents were synthesized and evaluated as EGFR inhibitors, and most showed significant inhibitory potency against EGFR kinase. In particular, compound 6g possessed potent inhibitory activity against EGFR wild-type (IC50  = 5 nM), and strong antiproliferative activity against HCC827 and Ba/F3 (L858R) cell lines. Kinase profiling against a panel of 365 kinases showed that 6g was highly selective for EGFR. Furthermore, 6g showed desirable properties in assays of liver microsome metabolic stability and cytochromes P450 inhibition and preliminary pharmacokinetic study...
February 16, 2018: Bioorganic & Medicinal Chemistry
Agnieszka Zagorska, Anna Partyka, Adam Bucki, Alicja Gawalska, Anna Czopek, Maciej Pawlowski
BACKGROUND: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases. OBJECTIVE: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery...
March 8, 2018: Current Medicinal Chemistry
Shenghai Guo, Fang Wang, Li Tao, Xinying Zhang, Xuesen Fan
A simple and practical procedure for the selective preparation of 3H-indol-3-one and indolo[1,2-c]quinazoline derivatives through copper-catalyzed aerobic oxygenation and intramolecular cyclization reactions of 2-(2-amidoaryl)-1H-indoles in the presence of acid has been disclosed. Interestingly, the reaction outcomes are exclusively dependent on the reaction medium employed. With DMF as the solvent, the amide moiety of indole substrates could act as an auxiliary to enable the indole's oxygenation reaction with molecular oxygen from air as the oxidant to give 3H-indol-3-one derivatives in a highly selective manner...
March 7, 2018: Journal of Organic Chemistry
Premnath Dhanaraj, Akila Devadas, Indiraleka Muthiah
Epigenetic characterization studies have clearly shown that the association of genital Human Papilloma Virus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. Even though all the strains of Human Papilloma Virus can cause cancer, the high-risk strains can cause severe cancer in a human. The E6 and E7 protein are responsible for the carcinogenic property of HPV. Among these two proteins, the HPV E7 protein plays a major role in the viral life cycle by allowing the virus to replicate in differentiating epithelial cells...
February 27, 2018: Computational Biology and Chemistry
M Srinivas, Anup Singh Pathania, Priya Mahajan, Praveen K Verma, Santosh S Chobe, Fayaz A Malik, Amit Nargotra, Ram A Vishwakarma, Sanghapal D Sawant
A strategy for construction of medicinally important 1,4-substituted 1H-1,2,3-triazolo-quinazolin-4(3H)-ones has been devised and presented here. The compounds have been synthesized using one-pot multicomponent strategy under microwave assisted conditions. Triazolyl-quinazolinone based D-ring modified analogs are designed based on IC87114 scaffold, which is first known isoform selective inhibitor of PI3Kδ. Herein, we identified two triazolyl-quinazolinone compounds (5a and 5l) based on same scaffold with PI3Kγ specific inhibitory potential, the selectivity towards this isoform is well supported by in silico results, wherein, these compounds show better interaction and affinity and inhibitory activity for PI3Kγ rather than PI3Kδ...
February 16, 2018: Bioorganic & Medicinal Chemistry Letters
Shun Huang, Yanjiang Han, Min Chen, Kongzhen Hu, Yongshuai Qi, Penghui Sun, Men Wang, Hubing Wu, Guiping Li, Quanshi Wang, Zhiyun Du, Kun Zhang, Suqing Zhao, Xi Zheng
Epidermal growth factor receptor (EGFR) has gained significant attention as a therapeutic target. Several EGFR targeting drugs (Gefitinib and Erlotinib) have been approved by US Food and Drug Administration (FDA) and have received high approval in clinical treatment. Nevertheless, the curative effect of these medicines varied in many solid tumors because of the different levels of expression and mutations of EGFR. Therefore, several PET radiotracers have been developed for the selective treatment of responsive patients who undergo PET/CT imaging for tyrosine kinase inhibitor (TKI) therapy...
September 1, 2017: Bioorganic & Medicinal Chemistry Letters
Xiao-Fei Shang, Susan L Morris-Natschke, Guan-Zhou Yang, Ying-Qian Liu, Xiao Guo, Xiao-Shan Xu, Masuo Goto, Jun-Cai Li, Ji-Yu Zhang, Kuo-Hsiung Lee
To follow-up on our prior Part I review, this Part II review summarizes and provides updated literature on novel quinoline and quinazoline alkaloids isolated during the period of 2009-2016, together with the biological activity and the mechanisms of action of these classes of natural products. Over 200 molecules with a broad range of biological activities, including antitumor, antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, hepatoprotective, antioxidant, anti-asthma, antitussive, and other activities, are discussed...
February 27, 2018: Medicinal Research Reviews
Zhuo Liu, Luhong Wang, Min Feng, Yuanyuan Yi, Wenhan Zhang, Wenjuan Liu, Lei Li, Zhihao Liu, Yanxia Li, Xiaodong Ma
A new class of acrylamide-substituted quinazoline derivatives with enhanced inhibitory activity against mutant EGFR T790M enzyme were synthesized. Among them, compound 10b displayed the strongest inhibitory potency to block the phosphorylation of the EGFR T790M enzyme, with an IC50 value of 4.3 nM. Compared with the lead compound gefitinib, compound 10b significantly strengthened the activity against EGFR T790M (194 times higher). Furthermore, compound 10b only exhibited moderate activity against wild type EGFR, with an IC50 of 105...
February 15, 2018: Bioorganic Chemistry
Aniket Mishra, Upasana Mukherjee, Tripta Kumari Vats, Indubhusan Deb
Ir(III)-catalyzed unprecedented mild C-H amidation for weakly co-ordinating cyclic N-sulfonyl ketimines, accelerated by a mono protected L-amino acid, has been developed. The method uses 1,4,2-dioxazol-5-ones as the robust amidating reagent in conjunction with a catalytic amount of silver triflate. It is highly selective, and does not require stoichiometric amount of oxidants or additives. A series of mechanistic experiments were performed to gain some insights into reaction mechanism. The strategy provides easy access to novel benzosultam-quinazoline and benzosultam-quinazolinone hybrid scaffolds endowed with pharmaceutically relevant features...
February 23, 2018: Journal of Organic Chemistry
Minhao Lou, Zhihong Deng, Xuechun Mao, Yang Fu, Qin Yang, Yiyuan Peng
An efficient method for the synthesis of isoquinolino[1,2-b]quinazolin-8-one derivatives and 12-methyl-12H-isoindolo[1,2-b]quinazoline-10-one derivatives is described herein. With rhodium catalysis, the desired products are obtained through a sequence reaction of C-H activation-based alkenylation and intramolecular aza-Heck-type cyclization. The developed method has a wide range of substrate tolerance under mild conditions and provides an alternative for the structural elaboration of quinazoline compounds.
February 22, 2018: Organic & Biomolecular Chemistry
Chao Ma, Naoko Higashi, Kyoko Ishiguro, Ying Zhao, Linkui Zhang, Chenwen Zhao, Maosheng Cheng, Hisae Oku
Linarinic acid, (-)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid (4a), was isolated from the ethanol extract of Linaria vulgaris Mill. In our previous study, a series of tetrahydropyrrolo[2,1-b]quinazoline derivatives 4b, 4c, 5a, 5b, 6a and 6b that were structurally related to 4a and evaluated as neuroprotective agents were synthesized. The aim of the present study was to investigate the novel features of these compounds. We examined their allergy-preventive effects using an in vivo assay system we developed previously, that monitors a decrease in blood flow in the tail vein of mice subjected to sensitization with hen egg-white lysozyme...
February 21, 2018: Journal of Natural Medicines
Kavitha Donthiboina, Hari Krishna Namballa, Siddiq Pasha Shaik, Jagadeesh Babu Nanubolu, Nagula Shankaraiah, Ahmed Kamal
An iodine promoted tandem oxidative condensation of benzylamines and 2-methylquinazolin-4-(3H)-ones was developed to yield imidazo[1,5-a]quinazolin-5(4H)-ones via dual C(sp3 )-H amination under metal free conditions in a greener way using molecular oxygen as a terminal oxidant. This tandem transformation provides an efficient approach to construct various functionalized imidazo[1,5-a]quinazolin-5(4H)-ones in a straightforward manner via a sequential amination-oxidation-annulation-aromatisation.
February 19, 2018: Organic & Biomolecular Chemistry
Xiu-Li Su, Shu Xu, Yu Shan, Min Yin, Yu Chen, Xu Feng, Qi-Zhi Wang
In this research, we investigated the profile and bioactivities of quinazoline alkaloids, a class of natural products boasting multiple bioactivities, from the unripe fruit of Evodia rutaecarpa (Juss.) Benth. Three new quinazoline alkaloids, evodiamide A (1), evodiamide B (2), and evodiamide C (3), as well as eight known quinazolines, were isolated from the MeOH extract of E. rutaecarpa. The new compounds are rare quinazolinedione derivatives with linked heterocyclic nuclei. Among these quinazolines, rhetsinine (8) showed potential as a pesticide and exhibited excellent inhibition against Xanthomonas oryzae pv...
February 14, 2018: Fitoterapia
Farhad Shirini, Masoumeh Mazloumi, Mohadeseh Seddighi
In this work, an efficient and green procedure have been described for the synthesis of tetrahydrobenzimidazo[2,1-b]quinazolin-1(2H)-one derivatives using nanoporous sodium montmorillonite clay (Na+-MMT) modified with 1-methyl-3-(trimethoxysilylpropyl)-imidazolium hydrogen sulfate (Na+-MMT-[pmim]HSO4). The procedure gave the products in excellent yields in very short reaction times under solvent-free condition. Also this catalyst can be reused for six times without considerable loss of its catalytic activity...
February 1, 2018: Journal of Nanoscience and Nanotechnology
Yan Zhang, Jian-Quan Liu, Xiang-Shan Wang
CuI functions as a mild Lewis acid catalyst to promote the condensation and cyclization reaction of 2-amino-N-(2-hydroxyphenyl)benzamide and 2-bromobenzaldehyde to build the quinazoline moiety first. With the addition of Cs 2 CO 3 , it also can catalyse the subsequent intramolecular Ullmann type reaction to give 16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-ones in good yields.
February 15, 2018: Organic & Biomolecular Chemistry
Tianxiao Wu, Yu Pang, Jing Guo, Wenbo Yin, Mingyue Zhu, Chenzhou Hao, Kai Wang, Jian Wang, Dongmei Zhao, Maosheng Cheng
A series of novel 2,4-diaminoquinazoline derivatives were designed, synthesized, and evaluated as p21-activated kinase 4 (PAK4) inhibitors. All compounds showed significant inhibitory activity against PAK4 (half-maximal inhibitory concentration IC 50 < 1 μM). Among them, compounds 8 d and 9c demonstrated the most potent inhibitory activity against PAK4 (IC 50 = 0.060 μM and 0.068 μM, respectively). Furthermore, we observed that compounds 8 d and 9c displayed potent antiproliferative activity against the A549 cell line and inhibited cell cycle distribution, migration, and invasion of this cell line...
February 14, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Hatem A Abuelizz, Rabab A El-Dib, Mohamed Marzouk, Rashad Al-Salahi
Previously, seventeen 2-phenoxy-benzo[g][1,2,4]triazolo[1,5-a]quinazoline derivatives were prepared and characterized by physicochemical and spectral means. This study was conducted to evaluate their activities in vitro against five Gram-negative and five Gram-positive of clinically pathogenic bacterial strains and ten fungal strains. The antimicrobial activity was assessed, and the minimum inhibitory concentration values of the tested compounds were determined in μg ml-1 , using the diffusion agar technique...
February 9, 2018: Microbial Pathogenesis
Elsa Forcellini, Sophie Boutin, Carole-Anne Lefebvre, Elnur Elyar Shayhidin, Marie-Chloé Boulanger, Gabrielle Rhéaume, Xavier Barbeau, Patrick Lagüe, Patrick Mathieu, Jean-François Paquin
The ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) was recently shown to promote mineralization of the aortic valve, hence, its inhibition represents a significant target. A quinazoline-4-piperidine sulfamide compound (QPS1) has been described as a specific and non-competitive inhibitor of NPP1. We report herein the synthesis and in vitro inhibition studies of novel quinazoline-4-piperidine sulfamide analogues using QPS1 as the lead compound. Of the 26 derivatives prepared, four compounds were found to have Ki < 105 nM against human NPP1...
February 2, 2018: European Journal of Medicinal Chemistry
Yaling Zhang, Li Chen, Hongjiang Xu, Xiabing Li, Lijun Zhao, Wei Wang, Baolin Li, Xiquan Zhang
A series of novel 6,7-dimorpholinoalkoxy quinazoline derivatives was designed, synthesized and evaluated as potent EGFR inhibitors. Most of synthesized derivatives exhibited moderate to excellent antiproliferative activities against five human tumor cell lines. Compound 8d displayed the most remarkable inhibitory activities against tumor cells expressing wild type (A431, A549 and SW480 cells) or mutant (HCC827 and NCI-H1975 cells) epidermal growth factor receptor (EGFR) (with IC50 values in the range of 0...
February 1, 2018: European Journal of Medicinal Chemistry
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