- Potential of substituted quinazolines to interact with multiple targets in the treatment of cancer
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The efficacy of quinazoline-based antiglioma agents has been attributed to their effects on microtubule dynamics.1,2 The design, synthesis and biological evaluation of quinazolines as potent inhibitors of multiple intracellular targets, including microtubules and multiple RTKs, is described. In addition to the known ability of quinazolines 1 and 2 to cause microtubule depolymerization, they were found to be low nanomolar inhibitors of EGFR, VEGFR-2 and PDGFR-β. Low nanomolar inhibition of EGFR was observed for 1–3 and 9–10. Compounds 1 and 4 inhibited VEGFR-2 kinase with activity better than or equal to that of sunitinib. In addition, compounds 1 and 2 had similar potency to sunitinib in the CAM angiogenesis assay. Multitarget activities of compounds in the present study demonstrates that the quinazolines can affect multiple pathways and could lead to these agents having antitumor potential caused by their activity against multiple targets.
- Choudhary, Shruti,Doshi, Arpit,Luckett-Chastain, Lerin,Ihnat, Michael,Hamel, Ernest,Mooberry, Susan L.,Gangjee, Aleem
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Read Online
- Development of certain new 2-substituted-quinazolin-4-ylaminobenzenesulfonamide as potential antitumor agents
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Carbonic anhydrases (CA I, II, IX and XII) are known to be highly expressed in various human malignancies. CA IX is overexpressed in colorectal cancer specifically in hereditary nonpolyposis colorectal cancer. Inhibition of CA activity by small molecular CA inhibitor like sulphonamides, sulphonamide derivative (SU.D2) or HIF1a inhibitor Chetomin leads to inhibition of tumorigenesis. Eighteen new quinazolin-4-sulfonamide derivatives were prepared and characterized by means of IR, NMR and mass spectra. Certain selected derivatives were tested for their ability to inhibit four isoforms of the metalloemzyme CA, namely, CA I, CA II, CA IX and CA XII. Compound 3c was found to be highly effective in inhibiting the cancer cell proliferation. 3c decreased cell viability of human HT-29 cells in dose and time dependent manner and with IC50 of 5.45 mM. Moreover, it was tested on metastatic colon cancer cell SW-620 where it was found to be equally effective on human SW-620 cells. This novel compound inhibited the CA IX and CA XII protein expression in HT-29 cells without affecting CA I and CA II expression. These findings indicate that 3c inhibits cellular proliferation in two human colon cancer cells by specifically targeting the CA IX and CA XII expression.
- Alafeefy, Ahmed M.,Ahmad, Rehan,Abdulla, Maha,Eldehna, Wagdy M.,Al-Tamimi, Abdul-Malek S.,Abdel-Aziz, Hatem A.,Al-Obaid, Omar,Carta, Fabrizio,Al-Kahtani, Abdulla A.,Supuran, Claudiu T.
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Read Online
- Discovery of a Series of Hydroxamic Acid-Based Microtubule Destabilizing Agents with Potent Antitumor Activity
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Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative activity of these MDAs depended on the presence of hydroxamic acid groups, but their inhibitory effects on HDAC were lost. Among them, 12b showed favorable metabolism stability, high bioavailability, and potent antitumor activity in multidrug-resistant cell lines and A2780/T xenograft model. More importantly, in the patient-derived xenograft models of triple-negative breast cancer and osimertinib-resistant non-small-cell lung cancer, both 20 mg/kg oral and 10 mg/kg intravenous administration of 12b could induce more than 70% tumor inhibition without obvious toxicity. Overall, we discovered that 12b, as a novel MDA based on hydroxamic acid, could serve as a potential MDA for further investigation.
- Bai, Peng,Chen, Lijuan,Kuang, Shuang,Liu, Jiang,Liu, Yan,Qiu, Qiang,Shi, Mingsong,Si, Wenting,Su, Zhengying,Tang, Minghai,Yan, Wei,Yang, Jianhong,Yang, Linyu,Yang, Zhuang,Ye, Haoyu,Zhang, Wanhua,Zhu, Zejiang
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p. 15379 - 15401
(2021/11/01)
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- Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors
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The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
- Chen, Zhe-Sheng,Dai, Qing-Qing,Li, Guo-Bo,Liu, Hong-Min,Liu, Hui,Wang, Bo,Wang, Shaomeng,Yu, Bin,Yuan, Shuo,Zhang, Jing-Ya,Zhang, Xiao-Nan,Zuo, Jia-Hui
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p. 14895 - 14911
(2021/10/12)
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- Preparation and application of substituted pyrazole compound containing pyriminostrobin
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The invention discloses a substituted pyrazole compound containing pyrimidine amine as shown in a general formula I. The definition of each substituent in the formula is described in the description. The compounds of the invention have a broad spectrum of sterilization. The insecticidal acaricidal activity has an excellent control effect on cucumber downy mildew, wheat powdery mildew, corn rust, rice blast, cucumber anthracnose and the like. The compounds of the invention exhibit good insecticidal activity at the same time.
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- Novel 3-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)quinazolin-4(3H)-ones and N-(1-benzylpiperidin-4-yl)quinazolin-4-amines and its use
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The present invention relates to novel 3 - ((1- benzyl - 1111.1 , 2, 3- triazole -4 - yl) methyl) quinazol -4 (3H) - won and N - (1- benzylpiperi -4 - yl) quinazoline -4 - amine and the use thereof. The present invention is more specifically described below. [AChE] The invention relates to novel Acetylcholine esterase ((3 - benzyl - 1111.1, 1- triazole 2,3- yl) methyl) quinazolin -4 - (3H) -4 and - won (N - benzylpiperi 1- yl) -4 - quinazoline -4 - amine and their use as therapeutic agents for neurological disorders.
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- Design, Synthesis, Antibacterial Activity, and Mechanisms of Novel 1,3,4-Thiadiazole Derivatives Containing an Amide Moiety
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To discover novel antibacterial agents, a series of novel 1,3,4-thiadiazole derivatives containing an amide moiety were designed and synthesized, and their antibacterial activities were tested. Compound 30 was designed and synthesized according to the CoMFA model. Compound 30 exhibited higher antibacterial activities against Xanthomonas oryzae pv. oryzicola and Xanthomonas oryzae pv. oryzae, with EC50 values of 2.1 and 1.8 mg/L, respectively, which were superior to those of thiodiazole copper (99.6 and 92.5 mg/L). The protective and curative activities of compound 30 against rice bacterial leaf blight were 51.3 and 46.1%, respectively, which were better than those of thiodiazole copper (37.8 and 38.5%). The protective and curative activities of compound 30 against rice bacterial leaf streak were 45.9 and 40.5%, respectively, which were better than those of thiodiazole copper (36.2 and 31.1%). In addition, the protective activity of compound 30 against rice bacterial leaf streak was related to increased activities of related defense enzymes and upregulated the differentially expressed proteins of the glycolysis/gluconeogenesis pathway.
- Wu, Zhibing,Shi, Jin,Chen, Jixiang,Hu, Deyu,Song, Baoan
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p. 8660 - 8670
(2021/08/20)
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- Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities
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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
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- SUBSTITUTED PYRIMIDINE COMPOUND AND PREPARATION METHOD AND USE THEREOF
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The present invention discloses a substituted pyrimidine compound. The structure is shown in general formula I. The definition of each substituent in the formula is described in the description. The compound of the present invention has broad-spectrum fungicidal, insecticidal and acaricidal activity, and has excellent control effects on cucumber downy mildew, powdery mildew, corn rust, anthrax, rice blast, aphids, Tetranychus cinnabarinus and the like.
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Paragraph 0263-0264
(2021/01/29)
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- Discovery of quinazoline derivatives as a novel class of potent and in vivo efficacious LSD1 inhibitors by drug repurposing
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Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC50 = 35.80 μM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC50 = 0.69 μM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.
- Li, Zhonghua,Li, Zhongrui,Ma, Jinlian,Miao, Jinxin,Qin, Tingting,Yang, Nian,Zhang, Xinhui,Zhang, Zhenqiang,Zhao, Taoqian,Zhao, Xuan
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- Novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments: Design, synthesis and bioactivity
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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
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- 4-aminoquinazoline phenyl ether compound and application thereof
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The invention provides a 4-aminoquinazoline phenyl ether compound. The structural formula of the 4-aminoquinazoline phenyl ether compound is shown as a formula I which is described in the specification. The compound shown as the formula I has excellent biological activity on agricultural harmful mites and lepidoptera pests such as plutella xylostella and can be used for preventing and treating theagricultural harmful mites and pests.
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Paragraph 0021; 0024-0025
(2020/05/02)
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- Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivatives
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Based on the structural modification of molecular-targeted agent sorafenib, a series of quinazolinyl-arylurea derivatives were synthesized and evaluated for their anti-proliferative activities against six human cancer cell lines. Compared with other cell lines tested, T24 was more sensitive to most compounds. Compound 7j exhibited the best profile with lower IC50 value and favorable selectivity. In this study, we focused on 7j-induced death forms of T24 cells and tried to elucidate the reason for its potent proliferative inhibitory activity. Compound 7j treatment could trigger three different cell death forms including apoptosis, ferroptosis, and autophagy; which form would occur depended on the concentrations and incubation time of 7j: (1) Lower concentrations within the initial 8 h of 7j treatment led to apoptosis-dependent death. (2) Ferroptosis and autophagy occurred in the case of higher concentrations combining with extended incubation time through effectively regulating the Sxc?/GPx4/ROS and PI3K/Akt/mTOR/ULK1 pathways, respectively. (3) The above death forms were closely associated with intracellular ROS generation and decreased mitochondrial membrane potential induced by 7j. In molecular docking and structure-activity relationship analyses, 7j could bind well to the active site of the corresponding receptor glutathione peroxidase 4 (GPx4). Compound 7j could be a promising lead for molecular-targeted anti-bladder cancer agents’ discovery.
- Chen, Jia-Nian,Li, Ting,Cheng, Li,Qin, Tai-Sheng,Sun, Ye-Xiang,Chen, Chu-Ting,He, Yue-Zhen,Liu, Guang,Yao, Di,Wei, Ying,Li, Qiu-Yin,Zhang, Guang-Ji
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- Spirocyclic compound containing pyrimidine and application thereof
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The invention discloses a pyrimidine-containing spiro compound, structure as shown in a general formula I : The compound of the invention has a broad-spectrum bactericidal activity . and has an excellent control effect, on cucumber downy mildew, wheat powdery mildew, corn rust, rice blast, cucumber anthracnose and the like.
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- Design, synthesis, and anticancer activities of sodium quinazolin-4-diselenide compounds
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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
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p. 497 - 502
(2019/11/03)
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- 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
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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
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- Drug-like property optimization: Discovery of orally bioavailable quinazoline-based multi-targeted kinase inhibitors
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In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potent anticancer compound in MOLM-13 and MV4-11 leukemia models, as well as in colorectal and pancreatic animal models. As BPR1K871 lacks oral bioavailability, we continued searching for orally bioavailable analogs through drug-like property optimization. We optimized both the physicochemical properties (PCP) as well as in vitro rat liver microsomal stability of 1, with concomitant monitoring of aurora kinase enzyme inhibition as well as cellular anti-proliferative activity in HCT-116 cell line. Structural modification at the 6- and 7-position of quinazoline core of 1 led to the identification of 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor, which exhibits potent anti-proliferative activity against various cancer cell lines. Quinazoline 34 is selected as a promising oral lead candidate for further preclinical evaluation.
- Chang, Chun-Feng,Chen, Chun-Hwa,Chen, Pei-Yi,Coumar, Mohane Selvaraj,Hsieh, Hsing-Pang,Hsu, John T. A.,Kuo, Fu-Ming,Kuo, Po-Chu,Li, An-Siou,Li, Mu-Chun,Lin, Chin-Yu,Lin, Shu-Yu,Lin, Wen-Hsing,Song, Jen-Shin,Wang, Sing-Yi,Yang, Chen-Ming,Yeh, Teng-Kuang
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- IDENTIFICATION AND USE OF ERK5 INHIBITORS
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The present invention covers heterocyclic compounds of general formula (I) in which T, U, Y, Z, R1 and R3 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer disorders, as a sole agent or in combination with other active ingredients.
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Page/Page column 51; 93
(2019/10/01)
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- TOLL-LIKE RECEPTOR 8 (TLR8)-SPECIFIC ANTAGONISTS AND METHODS OF MAKING AND USES THEREOF
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Toll-like receptor 8 (TLR8)-specific inhibitors and methods of using the same in individuals having an autoimmune disease or an inflammatory disorder.
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Page/Page column 63
(2019/05/22)
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- Synthesis and mode of action studies of novel {2-(3-R-1H-1,2,4-triazol-5-yl)phenyl}amines to combat pathogenic fungi
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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
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- Novel quinazoline EGFR inhibitor, and preparation method and application thereof
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A novel quinazoline EGFR inhibitor, and a preparation and an application thereof belong to the field of synthesis of medicines. The novel quinazoline EGFR inhibitor has a general formula shown in thedescription; and in the general formula, R is one from H, F, Cl, Br, and I, and R1 and R2 are same to or different from each other, and are respectively selected from H, a nitro group, an amino group,a hydroxyl group, a 2-methoxyethoxy group, a C1-C4 alkoxy group and a C1-C4 alkyl group. The novel quinazoline EGFR inhibitor is different from existing quinazoline inhibitors with the 4-position substituted with various anilines, and is designed and synthesized by substituting the 4-position of a quinazoline skeleton with a broadly bioactive thienylmethylamine and reasonably modifying the 6-position and the 7-position with groups not including an electrophilic acrylamide bond in order to avoid covalent bonds with EGFR. Compared with existing antitumor drugs, the above compound can significantly inhibit EGFR phosphorylation, and has excellent anti-proliferative activity against EGFR overexpressing tumor cells (such as A431 and MCF-7).
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Paragraph 0026; 0029
(2019/10/01)
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- Synthesis, Crystal Structure, and Agricultural Antimicrobial Evaluation of Novel Quinazoline Thioether Derivatives Incorporating the 1,2,4-Triazolo[4,3- a]pyridine Moiety
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A total of 22 quinazoline thioether derivatives incorporating a 1,2,4-triazolo[4,3-a]pyridine moiety were designed, synthesized, and evaluated as antimicrobial agents in agriculture. Among these compounds, the chemical structure of compound 6l was further confirmed via single-crystal X-ray diffraction analysis. The bioassay results revealed that some of the compounds possessed noticeable in vitro antibacterial activities against the tested phytopathogenic bacteria. For example, compounds 6b and 6g had EC50 values as low as 10.0 and 24.7 μg/mL against Xanthomonas axonopodis pv. citri (Xac), respectively, which were significantly better than that of the commercial agrobactericide bismerthiazol (56.9 μg/mL). Particularly, compound 6b was also found to be capable of suppressing the pathogenic bacterium Xanthomonas oryzae pv. oryzae (Xoo) approximately 12-fold more potent than control bismerthiazol, in terms of their EC50 values (7.2 versus 89.8 μg/mL). Importantly, the most active compound 6b turned out to be one with the highest hydrophilicity and the lowest molecular weight within the series. In vivo bioassays further showed the application prospect of 6b as a promising plant bactericide for controlling Xoo. Additionally, in vitro antifungal activities of these compounds were also evaluated at the concentration of 50 μg/mL. Overall, the present study demonstrated the potential of 1,2,4-triazolo[4,3-a]pyridine-bearing quinazoline thioether derivatives as efficient agricultural antibacterial agents for crop protection.
- Fan, Zhijiang,Shi, Jun,Luo, Na,Ding, Muhan,Bao, Xiaoping
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p. 11598 - 11606
(2019/10/19)
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- Synthesis and biological evaluation of some novel thiophene-bearing quinazoline derivatives as EGFR inhibitors
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Background: With the approval of gefitinib, erlotinib, afatinib, and osimertinib for clinical use, targeting Epidermal Growth Factor Receptor (EGFR) has been intensively pursued. Similar to most therapies, challenges related to the treatment resistance against these drugs have emerged over time, so new EGFR Tyrosine Kinase Inhibitors (TKIs) need to be developed. This study aimed to investigate the potential use of a series of thiophene-bearing quinazoline derivatives as EGFR inhibitors. We designed and synthesized nine quinazolin derivatives, among which five compounds (5e, 5f, 5g, 5h, and 5i) were reported for the first time. Methods: Two cancer cell lines, A431 (overexpressing EGFR) and A549 (EGFR wild-type and K-ras mutation), were treated by these compounds and subjected to MTT assay. The A431 cells were selected for further treatment (5e) and Western blot analysis. Results: Although the compounds exerted no obvious effects on the proliferation of A549 cells, seven out of the nine compounds significantly inhibited the growth of A431 cells. In particular, the IC50 values of 5e and erlotinib were nearly equal. Western blot results showed that 5e significantly inhibited EGFR autophosphorylation in A431 cells. Structure-activity relationships indicated that quinazolines bearing 6,7-side chains were more potent than those unsubstituted at the 6,7-positions. Moreover, electron-withdrawing hydrophobic groups on the 5-position of the thiophene were preferred, such as chlorine or bromine atom. Conclusion: Nine 4-aminoquinazolin derivatives were designed, synthesized, and evaluated against A431 and A549 cell lines. Seven compounds significantly inhibited the growth of A431 cells. In particular, 5e possessed similar antitumor potency to that of erlotinib.
- Zou, Min,Jin, Bo,Liu, Yanrong,Chen, Huiping,Zhang, Zhuangli,Zhang, Changzheng,Zhao, Zhihong,Zheng, Liyun
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p. 102 - 110
(2019/01/04)
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- HISTONE DEACETYLASE INHIBITOR, AND PREPARATION METHOD AND USE THEREOF
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A compound represented by Formula I or pharmaceutically acceptable salt thereof. The present invention relates to a 4-arylamino quinazoline hydroxamic acid compound having a histone deacetylase inhibitory activity, preparation method of the compound, pharmaceutical composition comprising the compound, and use of the compound and the pharmaceutical composition in the preparation of a histone deacetylase inhibitor medicine. The present invention aims at acquiring, via a medicine design and a synthetic technology, a series of selective histone deacetylase inhibitors having good hypotype selectivity and favorable pharmacokinetic characteristics based on optimization of an enzyme surface recognition region and connection region of 4-arylamino quinazoline, thus reducing an effect on normal tissues or cells while improving an antineoplastic activity of the normal tissues or cells.
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Paragraph 0282-0283
(2018/04/20)
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- Syntheses, antiviral activities and induced resistance mechanisms of novel quinazoline derivatives containing a dithioacetal moiety
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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
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p. 433 - 443
(2018/07/13)
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- Quinazoline-containing 1,4-pentadiene-3-ketone oxime ether derivative as well as preparation method and application thereof
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The invention discloses a quinazoline-containing 1,4-pentadiene-3-ketone oxime ether derivative. The quinazoline-containing 1,4-pentadiene-3-ketone oxime ether derivative is characterized in that thegeneral formula is shown in the description, wherein R1 is phenyl, substituted phenyl or substituted heteroaromatic ring radical; R2 is phenyl, substituted phenyl or substituted heteroaromatic ring radical; R3 is one or more of hydrogen atoms, methoxyl groups, nitryl groups, methyl groups, trifluoromethyl groups or halogen atoms at 5-, 6-, 7- or 8-position of quinazoline. The compound provided bythe invention has good treatment and protection effects on cucumber mosaic virus (CMV) and tobacco mosaic virus (TMV), has higher plant virus activity resistance, and can be applied to preparation ofpesticides for resisting plant viruses.
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Paragraph 0056-0057
(2018/04/01)
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- Pyrimidine-containing substituted azole compounds and application thereof
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The invention discloses pyrimidine-containing substituted azole compounds with a structure as shown in a formula 1 in the description. In the formula 1, the definition of each substituent is enclosedin the description. The compounds disclosed by the invention have broad-spectrum bactericidal function and insecticidal and acaricidal activities, and have excellent control efficacy on cucumber downymildew, puccinia polysora, cucumber anthracnose and the like, in particular on cucumber downy mildew and puccinia polysora. Part of the compounds show certain insecticidal cavity on myzus persicae and tetranychus cinnabarinus at the same time. The pyrimidine-containing substituted azole compounds can be used for preparing bactericidal, insecticidal and acaricidal agents.
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- Substituted Pyrazole Compounds Containing Pyrimidine and Preparation Method and Use Thereof
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Disclosed are substituted pyrazole compounds containing pyrimidinyl as shown in Formula I: The definitions of each of the substituents can be seen in the description. The compounds of present invention have a good spectrum of bactericidal, insecticidal and acaricidal activity,and have good control effect on downy mildew of cucumber, powdery mildew of wheat, corn rust, rice blast, cucumber anthracnosis and the like. The compounds of present invention also show good insecticidal activity.
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- Substituted pyrazole compound containing pyrimidine, and preparation method and use thereof
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The invention discloses a substituted pyrazole compound containing pyrimidine, wherein the compound has a structure represented by the general formula I, and the definitions of substituents in the formula are defined in the specification. The compound has broad-spectrum bactericidal activity, and has excellent prevention and treatment effects on cucumber downy mildew, corn rust disease, rice blastand the like.
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- Novel hybrid molecules of quinazoline chalcone derivatives: Synthesis and study of In Vitro cytotoxic activities
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Background: A new series of quinazoline linked chalcone conjugates were synthesized and evaluated for their in vitro cytotoxicity. Methods: The quinazoline-chalcone derivatives (13a-r) have been prepared by the Claisen-Schmidt condensation of various substituted benzaldehydes (12a-r) with substituted l-(4-(3,4- dihydroquinazolin-4-ylamino)phenyl)ethanone (11a-b) in the presence of aqueous NaOH. Three potential compounds 13f, 13g and 13h exhibited cytotoxicity against leukemia (GI50 value of 1.07, 0.26 and 0.24 μM), Non-small lung (GI50 values of 2.05,1.32 and 0.23 μM), colon (GI50 values of 0.54, 0.34 and 0.34 μM) and breast (GI50 values of 2.17, 1.84 and 0.22 μM) cell line, respectively. Results and Conclusion: Based on these biological results, it is evident that compound 13h has the potential to be considered for further detailed studies either alone or in combination with existing therapies as potential anticancer agents.
- Thiriveedhi, Arunkumar,Nadh, Ratnakaram Venkata,Srinivasu, Navuluri,Kaushal, Kishore
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p. 757 - 765
(2018/06/26)
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- A quinazoline of containing 1, 4 - pentadiene -3 - oxime ether derivatives, preparation method and application thereof (by machine translation)
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The invention discloses a containing the quinazoline of 1, 4 - pentadiene - 3 - oxime ether derivatives, preparation method and application thereof, the general formula (I) are as follows: Wherein R1 , R2 Is phenyl, substituted phenyl or substituted aryl heterocyclic group; R3 In the quinazoline of 5, 6, 7 or 8 position containing more than one hydrogen atom, methoxy, nitro, methyl, trifluoromethyl or halogen atom. The compounds of the invention to liver cancer SMMC - 7721 cell has excellent inhibitory activity, and exhibits a high anti-tumor activity, can be used as potential anti-tumor pharmaceutical use. (by machine translation)
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Paragraph 0016; 0020
(2018/10/11)
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- Synthesis and biological evaluation of new tetramethylpyrazine-based chalcone derivatives as potential anti-Alzheimer agents
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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
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p. 1859 - 1866
(2018/07/31)
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- Model containing quinazoline sulfide chalcone derivatives preparation method and application of
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The invention discloses a compound with an effect of resisting plant viruses, namely a preparation method and biological activity for a chalcone derivative containing quinazoline thioether. The preparation method is used for synthesizing chalcone derivative containing quinazoline thioether by using vairous aromatic aldehydes, p-hydroxy phenyl ethyl ketone, o-aminobenzoic acid, formamide, thionyl chloride, potassium hydroxide and potassium carbonate as raw materials through six steps. The compounds M2, M6, M9 and M22 have relatively high protection, passivation and treatment effect to a tobacco mosaic virus (TMV), and can be used for preparing a novel pesticide for preventing plant virus diseases. According to a formula shown in the description, R is a benzene ring, a substituted aromatic ring and a substituted heterocyclic ring, o-position, m-position and p-position on the aromatic ring comprise one or more of methoxy groups, nitryl, methyl, trifluoromethyl, 2-chlorine-5-nitryl as well as halogen atoms; the halogen atoms can be fluorine, chlorine, bromine and iodine; the heterocyclic ring is a five-member ring, a substituted five-member ring or a six-member ring.
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- Design, Synthesis, Antiviral Activities of Novel Phosphonate Derivatives Containing Quinazoline Based on Chalone Motif
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Based on the structure of natural product chalone, a series of novel phosphonate derivatives were designed and synthesized through 1,4-hydrophosphinylation of α,β-unsaturated carbonyl compounds. Their structures were characterized by IR, NMR, MS, and elemental analysis. The antiviral activities against cucumber mosaic virus were evaluated for the first time. The bioassay results indicated that most compounds exhibited good protective activities, low curative activities, and weak inactive activities. The antiviral protective activities of compounds C2 and C5 were 55.1% and 56.8%, respectively, which are slightly higher than those of the commercial Ningnanmyin (49.3%) and Dufulin (53.1%). Moreover, compounds C2 and C9 exhibited moderate curative activities (42.6% and 46.6%). Therefore, the basic motif of C1 can be used as a new lead structure for developing antivirus agents.
- Zhang, Guo-Ping,Pan, Jian-Ke,Zhang, Jian,Wu, Zeng-Xue,Liu, Deng-Yue,Zhao, Lei
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p. 2548 - 2555
(2017/07/25)
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- A novel method for heterocyclic amide-thioamide transformations
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In this paper, we introduce a novel and convenient method for the transformation of heterocyclic amides into heteocyclic thioamides. A two-step approach was applied for this transformation: Firstly, we applied a chlorination of the heterocyclic amides to afford the corresponding chloroheterocycles. Secondly, the chloroherocycles and N-cyclohexyl dithiocarbamate cyclohexylammonium salt were heated in chloroform for 12 h at 61°C to afford heteocyclic thioamides in excellent yields.
- Fathalla, Walid,Ali, Ibrahim A. I.,Pazdera, Pavel
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p. 174 - 181
(2017/02/15)
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- A pyrazolyl pyrimidine compound and use thereof
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The present invention discloses a pyrazolyl pyrilamine compound, the compound has a structure as shown in formula (I), and the substituent groups in the (I) are as defined in the specification. The pyrazolyl pyrilamine compound has good control effects on downy mildew of cucumber, puccinia polysra, wheat powdery mildew and other diseases, and is especially better in the control effect on the downy mildew of cucumber.
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Paragraph 0347; 0351-0353
(2017/08/30)
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- Synthesis of novel 1,2,4-triazole derivatives containing the quinazolinylpiperidinyl moiety and: N -(substituted phenyl)acetamide group as efficient bactericides against the phytopathogenic bacterium Xanthomonas oryzae pv. oryzae
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A series of novel 1,2,4-triazole derivatives (7a-7p) containing the quinazolinylpiperidinyl moiety and N-(substituted phenyl)acetamide group were designed, synthesized and evaluated for their antimicrobial activities in vitro. These compounds were fully characterized by 1H NMR, 13C NMR, HRMS and IR spectra. Notably, the structure of compound 7p was further confirmed through the single-crystal X-ray diffraction method. The obtained bioassay results indicated that most of these compounds exhibited good to excellent antibacterial activities against the rice bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo). For example, compounds 7e, 7g, 7n, 7l, 7i, 7k, 7a and 7h had EC50 (half-maximal effective concentration) values of 34.5, 38.3, 39.0, 46.0, 47.5, 54.6, 55.0 and 58.2 μg mL-1 against the bacterium, respectively, which were significantly lower than the control agent Bismerthiazol (85.6 μg mL-1). Additionally, antifungal experiments demonstrated that all the compounds did possess weak inhibition capabilities against three phytopathogenic fungi at 50 μg mL-1, except in the cases of compounds 7e and 7p against the fungus Gibberella zeae. The above experimental results proved that 1,2,4-triazole derivatives bearing both a quinazolinylpiperidinyl fragment and N-(substituted phenyl)acetamide unit are promising candidates for the development of new agricultural bactericides against the pathogenic bacterium Xoo, deserving further investigation in the future.
- Yang, Lan,Bao, Xiao-Ping
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p. 34005 - 34011
(2017/07/17)
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- Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups
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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
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supporting information
p. 4885 - 4888
(2017/09/27)
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- A histone deacetylase inhibitor and its preparation and use (by machine translation)
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The invention provides a compound of formula I illustrated compound or its pharmaceutically acceptable salt, relates to has the histone deacetylase inhibitory activity of the 4 - aryl amino [...] novel class of compound, the preparation of the compounds, comprising the pharmaceutical composition and the compounds and pharmaceutical compositions in the preparation of histone deacetylase enzyme inhibitor drug in its class of use; aimed at through the drug design and synthesis means based on obtaining a series of 4 - aryl amino [...] surface of the cleat and linkage area optimization, with subtype selective and good medicine generation of dynamics characteristic of selective histone deacetylase inhibitors, in order to improve the anti-tumor activity at the same time to reduce the impact of the normal tissue or cells. (by machine translation)
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Paragraph 0438; 0439; 0440; 0441
(2017/02/17)
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- Contrast agents for applications including perfusion imaging
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The present invention is directed, in part, to compounds and methods for imaging the central nervous system or cancer, comprising administering to a subject a contrast agent which comprises a compound that binds MC-I, and an imaging moiety, and scanning the subject using diagnostic imaging.
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Page/Page column 67
(2016/09/12)
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- Facile and efficient synthesis and biological evaluation of 4-anilinoquinazoline derivatives as EGFR inhibitors
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Series of 4-anilinoquinazoline derivatives were conveniently and efficiently synthesized and their antitumor activities were evaluated by MTT assay in three human cancer cell lines: H1975, HepG2 and SMMC-7721. New compounds 19a-19h were designed and synthesized to seek for powerful EGFR inhibitors and to explore whether methyl group at C-2 position of quinazoline ring has a positive effect on EGFR inhibition. All the compounds of 19a-19h were found potent against all three cell lines and five compounds (19c, 19d, and 19f-19h) were found more potent against H1975 than gefitinib. SAR studies revealed that methyl group at C-2 position of quinazoline ring could significantly improve the antitumor potency of 4-anilinoquinazolines. The same conclusion was also drawn according to the results of Western blotting analysis. Among all the tested compounds, 19g exhibited extremely potent against H1975 with an IC50 value of 0.11 μM, remarkably lower than that of gefitinib (1.23 μM). The results of western blotting analysis showed that compounds 19c and 19g could notably inhibit the expression of phosphorylated EGFR, especially 19g, almost inhibited completely.
- Wang, Zheng,Wu, Xue,Wang, Li,Zhang, Jiao,Liu, Jianli,Song, Zhongxing,Tang, Zhishu
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p. 2589 - 2593
(2016/05/09)
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- Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents
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Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7g, 7m, 7o, 8e, 8g, and 8m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8g exhibited the strongest activity. In particular, compound 8g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure-activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8g may be a potent antitumor agent, representing a promising lead for further optimization.
- Chen, Jia-Nian,Wang, Xian-Fu,Li, Ting,Wu, De-Wen,Fu, Xiao-Bo,Zhang, Guang-Ji,Shen, Xing-Can,Wang, Heng-Shan
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- The combination of quinazoline and chalcone moieties leads to novel potent heterodimeric modulators of breast cancer resistance protein (BCRP/ABCG2)
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During the last decade it has been found that chalcones and quinazolines are promising inhibitors of ABCG2. The combination of these two scaffolds offers a new class of heterocyclic compounds with potentially high inhibitory activity against ABCG2. For this purpose we investigated 22 different heterodimeric derivatives. In this series only methoxy groups were used as substituents as these had been proven superior for inhibitory activity of chalcones. All compounds were tested for their inhibitory activity, specificity and cytotoxicity. The most potent ABCG2 inhibitor in this series showed an IC50 value of 0.19 μM. It possesses low cytotoxicity (GI50 = 93 μM), the ability to reverse MDR and is nearly selective toward ABCG2. Most compounds containing dimethoxy groups showed slight activity against ABCB1 too. Among these three compounds (17, 19 and 24) showed even higher activity toward ABCB1 than ABCG2. All inhibitors were further screened for their effect on basal ATPase activity. Although the basal ATPase activity was partially stimulated, the compounds were not transported by ABCG2. Thus, quinazoline-chalcones are a new class of effective ABCG2 inhibitors.
- Kraege, Stefanie,Stefan, Katja,Juvale, Kapil,Ross, Thomas,Willmes, Thomas,Wiese, Michael
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p. 212 - 229
(2016/04/26)
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- Ferulic acid ester derivative containing quinazoline, as well as preparation method and purpose of ferulic acid ester derivative
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The invention discloses a ferulic acid ester derivative containing quinazoline, as well as a preparation method and a purpose of the ferulic acid ester. A structural general formula (I) of the ferulic acid ester derivative containing the quinazoline is as follows: R1 is methyl, ethyl, n-propyl, isopropyl and normal-butyl; R2 is hydrogen, 6,7-dimethoxy and 6,7-bis-methoxyethoxy. The ferulic acid ester derivative containing the quinazoline can resist the cucumber mosaic virus, the tobacco mosaic virus, the southern rice black-streaked dwarf virus and the rice stripe virus.The structural general formula (I) is shown in the specification.
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- Synthesis, antiviral bioactivity of novel 4-thioquinazoline derivatives containing chalcone moiety
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A series of novel 4-thioquinazoline derivatives containing chalcone moiety were designed, synthesized and systematically evaluated for their antiviral activity against TMV. The bioassay results showed that most of these compounds exhibited moderate to good anti-TMV activity. In particular, compounds M2 and M6 possessed appreciable protection activities against TMV in vivo, with 50% effective concentration (EC50) values of 138.1 and 154.8 μg/mL, respectively, which were superior to that of Ribavirin (436.0 μg/mL). The results indicated that chalcone derivatives containing 4-thioquinazoline moiety could effectively control TMV. Meanwhile, the structure-activity relationship (SAR) of the target compounds, studied using the three-dimensional quantitative structure-activity relationship (3D-QSAR) method of comparative molecular field analysis (CoMFA) based on the protection activities against TMV, demonstrated that the CoMFA model exhibited good predictive ability with the cross-validated q2 and non-cross-validated r2 values of 0.674 and 0.993, respectively. Meanwhile, the microscale thermophoresis (MST) experimental showed that the compound M6 may interaction with the tobacco mosaic virus coat protein (TMV CP).
- Wan, Zhihua,Hu, Deyu,Li, Pei,Xie, Dandan,Gan, Xiuhai
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p. 11861 - 11874
(2015/08/18)
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- Discovery of quinazolin-4-amines bearing benzimidazole fragments as dual inhibitors of c-Met and VEGFR-2
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Both c-Met and VEGFR-2 are important targets for the treatment of cancers. In this study, a series of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinazolin-4- amine derivatives were designed and identified as dual c-Met and VEGFR-2 inhibitors. Among these compounds bearing quinazoline and benzimidazole fragments, compound 7j exhibited the most potent inhibitory activity against c-Met and VEGFR-2 with IC50 of 0.05 μM and 0.02 μM, respectively. It also showed the highest anticancer activity against the tested cancer cell lines with IC50 of 1.5 μM against MCF-7 and 8.7 μM against Hep-G2. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, which demonstrates that compound 7j is a potential agent for cancer therapy deserving further researching.
- Shi, Lei,Wu, Ting-Ting,Wang, Zhi,Xue, Jia-Yu,Xu, Yun-Gen
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p. 4735 - 4744
(2014/10/15)
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- CYCLIC SULFONAMIDE CONTAINING DERIVATIVES AS INHIBITORS OF HEDGEHOG SIGNALING PATHWAY
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The invention relates generally to the creation and use of cyclic sulfonamide containing derivatives to inhibit the hedgehog signaling pathway and to the use of those compounds for the treatment of hyperproliferative diseases and angiogenesis mediated diseases.
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Paragraph 0181
(2014/05/24)
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- Small-molecule phosphodiesterase probes: Discovery of potent and selective CNS-penetrable quinazoline inhibitors of PDE1
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PDE1 is a family of calcium-activated, dual substrate phosphodiesterases expressed in both the CNS and periphery that play a role in the integration of intracellular calcium and cyclic nucleotide signaling cascades. Exploration of the potential in targeting this family of enzymes to treat neuropsychiatric disorders has been hampered by a lack of potent, selective, and brain penetrable PDE1 inhibitors. To identify such compounds we used high-throughput screening, structure-based design, and targeted synthetic chemistry to discover the 4-aminoquinazoline 7a (PF-04471141) and the 4-indanylquinazoline 27 (PF-04822163) each of which are PDE1 inhibitors that readily cross the blood brain barrier. These quinazoline-based PDE1-selective inhibitors represent valuable new tools to study the biological processes regulated by PDE1 and to begin to determine the potential therapeutic utility of such compounds to treat neuropsychiatric disorders.
- Humphrey, John M.,Yang, Eddie,Ende, Christopher W. Am,Arnold, Eric P.,Head, Jenna L.,Jenkinson, Stephen,Lebel, Lorraine A.,Liras, Spiros,Pandit, Jayvardhan,Samas, Brian,Vajdos, Felix,Simons, Samuel P.,Evdokimov, Artem,Mansour, Mahmoud,Menniti, Frank S.
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p. 1290 - 1296
(2014/10/15)
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- Discovery of new HER2/EGFR dual kinase inhibitors based on the anilinoquinazoline scaffold as potential anti-cancer agents
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Herein, we designed and synthesized certain anilinoquinazoline derivatives bearing bulky arylpyridinyl, arylpropenoyl and arylpyrazolyl moieties at the 4′ position of the anilinoquinazoline, as potential dual HER2/EGFR kinase inhibitors. A detailed molecular modeling study was performed by docking the synthesized compounds in the active site of the epidermal growth factor receptor (EGFR). The synthesized compounds were further tested for their inhibitory activity on EGFR and HER2 tyrosine kinases. The aryl 2-imino-1,2-dihydropyridine derivatives 5d and 5e displayed the most potent inhibitory activity on EGFR with IC50 equal to 2.09 and 1.94 μM, respectively, and with IC50 equal to 3.98 and 1.04 μM on HER2, respectively. Furthermore, the anti-proliferative activity of these most active compounds on MDA-MB-231 breast cancer cell lines, known to overexpress EGFR, showed an IC50 range of 2.4 and 2.5 μM, respectively.
- Sadek, Maiada M.,Serrya, Rabah A.,Kafafy, Abdel-Hamid N.,Ahmed, Marawan,Wang, Feng,Abouzid, Khaled A. M.
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p. 215 - 222
(2014/04/03)
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- Synthesis and antitumor properties of novel curcumin analogs
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A series of novel curcumin (CC) analogs were synthesized by reacting substituted aldehydes with inter-mediates 4a and 4b. The inhibitory activities of these CC analogs were investigated on human cancer cells PC3, Bcap-37, and MGC-803 in vitro by MTT assay. The results showed that most of the title compounds displayed moderate to high levels of antitumor activities. Compound 5f, the most active CC analogs, has the IC50 values of 1.34 ± 0.28, 3.90 ± 0.36, and 0.86 ± 0.44 μM against the three human cancer cells assayed, respectively. Furthermore, subsequent fluorescence staining and flow cytometry analysis indicated compound 5f could induce apoptosis in PC3, Bcap-37, and MGC-803 cells, and the apoptosis ratio reachs the peak (27.1%) in MGC-803 cells at 24 h after treatment at 10 μM. Springer Science+Business Media 2013.
- Luo, Hui,Yang, Shengjie,Zhao, Qi,Xiang, Hongmei
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p. 2584 - 2595
(2014/05/06)
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