- Novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments: Design, synthesis and bioactivity
-
A series of novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether moieties were designed and synthesized. Their anticancer activities were evaluated by MTT assay, the results showed that most compounds exhibited extremely inhibitory effects against hepatoma SMMC-7721 cells. In particular, compounds Q2 and Q8 displayed the more potent inhibitory activity with IC50 values of 0.64 and 0.63 μM, which were better than that of gemcitabine (1.40 μM). Further mechanism studies indicated that compounds Q2, Q8, Q13 and Q19 could control the migration of SMMC-7721 cells effectively, and inhibit the proliferation of cancer cells by inhibiting the DNA replication. Western-blot results showed that compounds Q2 and Q8 induced irreversible apoptosis of SMMC-7721 cells by regulating the expression level of apoptose-related proteins. Those studies demonstrated that the penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments merited further research as potential anticancer agents.
- Su, Shijun,Chen, Mei,Li, Qin,Wang, Yihui,Chen, Shuai,Sun, Nan,Xie, Chengwei,Huai, Ziyou,Huang, Yinjiu,Xue, Wei
-
-
- Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities
-
A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.
- Zhang, Zixue,Zhang, Qingwei,Zhang, Hao,Jiao, Minru,Guo, Zheng,Peng, Xinyan,Fu, Lei,Li, Jianqi
-
-
- Design, synthesis, and anticancer activities of sodium quinazolin-4-diselenide compounds
-
Substituted 4-chloroquinazoline reacted with sodium diselenide to give novel sodium quinazoline-4-diselenide compounds. The reaction provides an efficient and facile approach to the synthesis of sodium quinazoline-4-diselenide compounds. Structures of title compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. MTT assay was adopted to show anticancer activities of the compounds. Compounds 5a and 5h showed good activities against cancer-cell lines MDA-MB-435, MDA-MB-231, A549, SiHa, and HeLa. In addition, 5a exhibited quite good anticancer effects on relative above cell lines with 10μM concentration compared with oxaliplatin and gefitinib of the commercial anticancer drugs.
- Zhang, Yuchun,Niu, Pengpeng,Wen, Quanwu,Sun, Lin,Wang, Weili,Xu, Shengguang,Liu, Gang
-
p. 497 - 502
(2019/11/03)
-
- Design, Synthesis and Bioevaluation of Two Series of 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines
-
Two series of 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-benzylpiperidin-4-yl)quinazolin-4-amines were designed initially as potential acetylcholine esterase inhibitors. Biological evaluation demonstrated that N-(1-benzylpiperidin-4-yl)quinazolin-4-amines significantly inhibited AChE activity. Especially, two compounds of them were found to be the most potent with relative AChE inhibition percentages of 87 percent in comparison to donepezil. The docking studies with AChE showed similar interactions between donepezil and four derivatives. N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines also exhibited significant DPPH scavenging effects. The two series of compound also exerted moderate to good cytotoxicity against three human cancer cell lines, including SW620 (human colon cancer), PC-3 (prostate cancer), and NCI?H23 (lung cancer), with 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one being the most cytotoxic agent. 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one significantly induced early apoptosis and arrested the SW620 cells at G2/M phase. From this study, two compounds of N-(1-benzylpiperidin-4-yl)quinazolin-4-amines could serve as new leads for further design and AChE inhibitors, while 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one could serve as a new lead for the design and development of more potent anticancer agents.
- Lan, Ta Thu,Anh, Duong Tien,Pham-The, Hai,Dung, Do Thi Mai,Park, Eun Jae,Jang, Sun Dong,Kwon, Joo Hee,Kang, Jong Soon,Thuan, Nguyen Thi,Han, Sang-Bae,Nam, Nguyen-Hai
-
-
- Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression
-
Aurora Kinase B is a serine-threonine kinase known to be overexpressed in several cancers, with no inhibitors approved for clinical use. Herein, we present the discovery and optimization of a series of novel quinazoline-based Aurora Kinase B inhibitors. The lead inhibitor SP-96 shows sub-nanomolar potency in Aurora B enzymatic assays (IC50 = 0.316 ± 0.031 nM). We identified the important pharmacophore features resulting in selectivity against receptor tyrosine kinases. Particularly, SP-96 shows >2000 fold selectivity against FLT3 and KIT which is important for normal hematopoiesis. This could diminish the adverse effect of neutropenia reported in the clinical trials of the Aurora B inhibitor Barasertib, which inhibits FLT3 and KIT in addition to Aurora B. Enzyme kinetics of SP-96 shows non-ATP-competitive inhibition which makes it a first-in-class inhibitor. Further, SP-96 shows selective growth inhibition in NCI60 screening, including inhibition of MDA-MD-468, a Triple Negative Breast Cancer cell line.
- Lakkaniga, Naga Rajiv,Zhang, Lingtian,Belachew, Binyam,Gunaganti, Naresh,Frett, Brendan,Li, Hong-yu
-
-
- Synthesis and mode of action studies of novel {2-(3-R-1H-1,2,4-triazol-5-yl)phenyl}amines to combat pathogenic fungi
-
Due to their high specificity and efficacy, triazoles have become versatile antifungals to treat fungal infections in human healthcare and to control phytopathogenic fungi in agriculture. However, azole resistance is an emerging problem affecting human health as well as food security. Here we describe the synthesis of 10 novel {2-(3-R-1H-1,2,4-triazol-5-yl)phenyl}amines. Their structure was ascertained by liquid chromatography–mass spectrometry, 1H and 13C NMR, and elemental analysis data. Applying an in vitro growth assay, these triazoles show moderate to significant antifungal activity against the opportunistic pathogen Aspergillus niger, 12 fungi (Fusarium oxysporum, Fusarium fujikuroi, Colletotrichum higginsianum, Gaeumannomyces graminis, Colletotrichum coccodes, Claviceps purpurea, Alternaria alternata, Mucor indicus, Fusarium graminearum, Verticillium lecanii, Botrytis cinerea, Penicillium digitatum) and three oomycetes (Phytophtora infestans GL-1, P. infestans 4/91; R+ and 4/91; R?) in the concentration range from 1 to 50 μg/ml (0.003–2.1 μM). Frontier molecular orbital energies were determined to predict their genotoxic potential. Molecular docking calculations taking into account six common fungal enzymes point to 14α-demethylase (CYP51) and N-myristoyltransferase as the most probable fungal targets. With respect to effectiveness, structure–activity calculations revealed the strong enhancing impact of adamantyl residues. The shown nonmutagenicity in the Salmonella reverse-mutagenicity assay and no violations of drug-likeness parameters suggest the good bioavailability and attractive ecotoxicological profile of the studied triazoles.
- Antypenko, Lyudmyla,Sadykova, Zhanar,Shabelnyk, Kostiantyn,Meyer, Fatuma,Kovalenko, Sergiy,Meyer, Vera,Garbe, Leif-Alexander,Steffens, Karl
-
-
- Syntheses, antiviral activities and induced resistance mechanisms of novel quinazoline derivatives containing a dithioacetal moiety
-
A series of novel quinazoline derivatives containing a dithioacetal moiety were designed and synthesized, and their structures were characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry. Bioassay results indicated that compound 4b exhibited remarkable protective activity against cucumber mosaic virus (CMV, EC50 = 248.6 μg/mL) and curative activity against potato virus Y (EC50 = 350.5 μg/mL), which were better than those of ningnanmycin (357.7 μg/mL and 493.7 μg/mL, respectively). Moreover, compound 4b could increase the chlorophyll content in plants, improve photosynthesis, and effectively induce tobacco anti-CMV activity.
- Xie, Dandan,Shi, Jing,Zhang, Awei,Lei, Zhiwei,Zu, Guangcheng,Fu, Yun,Gan, Xiuhai,Yin, Limin,Song, Baoan,Hu, Deyu
-
p. 433 - 443
(2018/07/13)
-
- Synthesis and biological evaluation of new tetramethylpyrazine-based chalcone derivatives as potential anti-Alzheimer agents
-
In the current study, a series of new ligustrazine-based chalcones was synthesized. For insertion of tetramethylpyrazine (TMP, also designated as ligustrazine) in chemical backbone of chalcone, a new ligustrazine-based aldehyde was prepared. New ketones were synthesized for inclusion of quinazolin-4-yl amino and pyrazin-2-yl amino moieties. The newly synthesized compounds were screened for acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases (MAO) inhibitory activities and also for in vitro cytotoxicity on PC12 cells. The effect of these compounds against amyloid β-induced cytotoxicity and aggregation was also investigated. The synthesized compounds effectively inhibited the related enzymes and also exhibited neuroprotective effects. Most of the compounds displayed better inhibitory potencies against Aβ aggregation than reference compounds. Some compounds such as 11e and 16b showed very potent effects on multiple targets exhibiting behavior as multifunctional anti-Alzheimer agents.
- Wang, Meng,Qin, Hua-Li,Leng, Jing,Ameeduzzafar,Amjad, Muhammad Wahab,Raja, Maria Abdul Ghafoor,Hussain, Muhammad Ajaz,Bukhari, Syed Nasir Abbas
-
p. 1859 - 1866
(2018/07/31)
-
- Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups
-
A series of hydroxamic acid-based HDACIs with 4-aminoquinazolinyl moieties as capping groups was profiled. Most compounds showed more potent HDACs inhibition activity than clinically used drug SAHA. Among them, compounds 5f and 5h selectively inhibited HDAC 1,2 over HDAC8, and showed strong activity in several cellular assays, not possessing significant toxicity to primary human cells and hERG inhibition. Strikingly, 5f possessed acceptable pharmacokinetic characteristics and exhibited significant antitumor activity in an A549 xenograft model study at well tolerated doses.
- Zhang, Qingwei,Li, Yang,Zhang, Baoyin,Lu, Bingliu,Li, Jianqi
-
supporting information
p. 4885 - 4888
(2017/09/27)
-
- PIPERIDINE SUBSTITUTED PYRAZOLO[1,5-A]PYRIMIDINE DERIVATIVES WITH INHIBITORY ACTIVITY ON THE REPLICATION OF THE RESPIRATORY SYNCYTIAL VIRUS (RSV)
-
The invention concerns novel substituted bicyclic pyrazolo pyrimidine compounds of formula (I) having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further conce
- -
-
Page/Page column 21
(2016/11/07)
-
- IRAK INHIBITORS AND USES THEREOF
-
The present invention provides quinazoline and quinoline compounds, compositions thereof, and methods of using the same. Also disclosed is the activity of such compounds as inhibitors of IRAK enzymes.
- -
-
-
- One-pot synthesis of 4-aminoquinazolines by hexamethyldisilazane-mediated reaction of quinazolin-4(3h)-ones with amines
-
Hexamethyldisilazane-mediated reaction of quinazolin-4(3H)-ones with primary amines led to facile formation of 4-aminoquinazolines through tandem silylation and substitution in a single pot. Excellent yields of the products (83-97%) and environmental friendliness (avoiding the use of chlorination reagents) are the advantages of this method. Copyright Taylor & Francis Group, LLC.
- Shen, Zhen-Lu,He, Xiao-Fei,Hong, Yi-Ming,Hu, Xin-Quan,Mo, Wei-Min,Hu, Bao-Xiang,Sun, Nan
-
experimental part
p. 3644 - 3653
(2011/10/09)
-
- Synthesis of some nitrogen mustrads (Quinazoline series)
-
Several nitrogen mustards with quinazoline moiety have been synthesised by condensation of 4-chloroquinazoline and 4,6- dichloroquinazoline with ethanol amine, diethanolamine and N-bis (2-chloroethyl) amine hydrochloride respectively.
- Sinha, Girish Kumar,Pandey, Bibhishan,Sinha, Alka
-
p. 1401 - 1406
(2011/10/13)
-
- Switching the Chemoselectivity in the Amination of 4-Chloroquinazolines with Aminopyrazoles
-
[Chemical equation presented] The chemoselectivity in the amination of 4-chloroquinazolines with 3-amino-1H-pyrazoles was studied. Under the conditions of Pd2(dba)3/ Xantphos/Na2CO3, 4-chloroquinazolines underwent selective amination with the cyclic secondary amino group of 3-amino-1H-pyrazoles. whereas 4-chloroquinazolines were exclusively aminated with the primary amino group of 3-amino-1H-pyrazoles via SNAr substitution In the presence of HCl.
- Shen, Zhenlu,Hong, Yiming,He, Xiaofei,Mo, Weimin,Hu, Baoxiang,Sun, Nan,Hu, Xinquan
-
supporting information; experimental part
p. 552 - 555
(2010/05/18)
-
- COMPOUND HAVING TGF-BETA INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
-
The present invention provides compounds of formula (I) or compounds of formula (II) and pharmaceutically acceptable salts or solvates thereof. An objective of the present invention is to provide compounds having TGF2 inhibitory activity.
- -
-
Page/Page column 49
(2010/11/24)
-
- Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
-
The present application describes modulators of MCP-1 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
- -
-
Page/Page column 38
(2010/02/11)
-
- Discovery of quinazolines as a novel structural class of potent inhibitors of NF-κB activation
-
We disclose here a new structural class of low-molecular-weight inhibitors of NF-κB activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-κB transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-κB transcriptional activation and TNF-α production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Nagasaki, Takahiro,Takahashi, Hirotada,Fukazawa, Tominaga,Hayashi, Hideya
-
p. 383 - 391
(2007/10/03)
-
- Structure-activity relationships of quinazoline derivatives: Dual-acting compounds with inhibitory activities toward both TNF-α production and T cell proliferation
-
We synthesized 4-chlorophenethylaminoquinazoline derivatives and evaluated their inhibitory activities toward both TNF-α production and T cell proliferation responses. Compound 2f, containing a piperazine ring at the C(7)-position of the quinazoline ring, exhibited more potent inhibitory activities toward both than the lead compound 1a. A smaller N-substituent in the piperazine ring was required for inhibition of TNF-α production.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Matsumoto, Mitsuhiro,Obara, Fumihiro,Nagasaki, Takahiro,Hayashi, Hideya
-
p. 545 - 548
(2007/10/03)
-
- The preparation and SAR of 4-(anilino), 4-(phenoxy), and 4-(thiophenoxy)-quinazolines: Inhibitors of p56(lck) and EGF-R tyorsine kinase activity
-
We report herein our preliminary results of a SAR study of quinazoline-based inhibitors of p56(lck) and EGF-R tyrosine kinase activity. The most potent inhibitor of p56(lck) identified, RPR-108518A (10), has an IC50 of 0.50 μM. The 3-chlorophenoxy- and 3-chlorothiophenoxy- derivatives 5 and 6 were also shown to be extremely potent EGF-R inhibitors.
- Myers, Michael R.,Setzer, Natalie N.,Spada, Alfred P.,Zulli, Allison L.,Hsu, Chin-Yi J.,Zilberstein, Asher,Johnson, Susan E.,Hook, Linda E.,Jacoski, Mary V.
-
p. 417 - 420
(2007/10/03)
-
- Tyrphostins IV - Highly potent inhibitors of EGF receptor kinase. Structure-activity relationship study of 4-anilidoquinazolines
-
Potent 4-anilido-substituted quinazolines which potently inhibit epidermal growth factor receptor (EGFR) kinase were prepared. Structure-activity relationship studies reveal high sensitivity to substitution at the aniline ring.
- Gazit, Aviv,Chen, Jeffrey,Harald, App,McMahon, Gerald,Hirth, Peter,Chen, Irit,Levitzki, Alexander
-
p. 1203 - 1207
(2007/10/03)
-