- 3,4-Dihydroquinazolin-8-yl-3-phenylurea Derivatives: Synthesis, VEGFR-2 Kinase Inhibiting Activity, and Molecular Docking
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Abstract: New 15 compounds have been synthesized targeting the highly conserved active site of VEGFR-2. Some of those have exhibited high anti-proliferation potency against tumor cells and inhibitory activity against VEGFR-2. One of the products (6h) has
- Jiang, Kunming,Li, Zhenjie,Liu, Zhihua,Song, Nali,Tang, Shiyun,Wu, Zhibang,Yang, Chen
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p. 1757 - 1766
(2021/11/01)
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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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- 4-Amino quinazoline compound as well as preparation method and application thereof
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The invention relates to a 4-amino quinazoline compound as well as a preparation method and application thereof. The compound has a general formula I) as shown in the specification, a quinazoline compound is taken as a basis, an aromatic ring methylene is introduced into the system for synthesizing a series of aromatic ring-containing methylene substituted 4-amino quinazoline compounds, the compound has a good inhibiting effect on pathogenic bacteria of plants, and has a good inhibiting effect on pathogenic bacteria such as xanthomonas oryzae, Xanthomonas citri and the like.
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Paragraph 0059; 0060
(2019/05/16)
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- 4-aminoquinazoline grafted acrylamide compounds, preparation method and application thereof
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The invention relates to 4-aminoquinazoline grafted acrylamide compounds, a preparation method and application thereof. The compounds have a structure shown as general formula (I) in the specification. According to the invention, a quinazoline compound is adopted as the basis, and acrylamido is introduced into the system to synthesize a series of acrylamido-containing substituted 4-aminoquinazoline compounds, and the compounds have a good inhibiting effect on plant pathogenic bacteria, and have good inhibiting effect on pathogenic bacteria directed at Xanthomonas oryzae pv. Oryzae, Xanthomonasaxonopodis pv. Citri, etc.
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Paragraph 0068; 0069
(2020/01/12)
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- Design, Synthesis, and Potency of Pyruvate Dehydrogenase Complex E1 Inhibitors against Cyanobacteria
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Safe and effective algaecides are needed to control agriculturally and environmentally significant algal species. Four series (6, 10, 17, and 21) of 29 novel 4-aminopyrimidine derivatives were rationally designed and synthesized. A part of 10, 17, and 21 displayed potent inhibition of Escherichia coli pyruvate dehydrogenase complex E1 (E. coli PDHc-E1) (IC50 = 2.12-18.06 μM) and good inhibition of Synechocystis sp. PCC 6803 (EC50 = 0.7-7.1 μM) and Microcystis sp. FACH 905 (EC50 = 3.7-7.6 μM). The algaecidal activity of these compounds positively correlated with their inhibition of E. coli PDHc-E1. In particular, 21l and 10b exhibited potent algaecidal activity against PCC 6803 (EC50 = 0.7 and 0.8 μM, respectively), values that were 2-fold increased compared to that of copper sulfate (EC50 = 1.8 μM), and showed the best inhibition of cyanobacterium PDHc-E1 (IC50 = 5.10 and 6.06 μM, respectively). 17h and 21e, the best inhibitors of E. coli PDHc-E1, were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. These results revealed that the improved inhibition of novel inhibitors compared with that of the lead compound I was due to the formation of a new hydrogen bond with Leu264 at the active site of E. coli PDHc-E1. The results proved the great potential to obtain effective algaecides via the rational design of PDHc-E1 inhibitors. [Figure Presented]
- Zhou, Yuan,Feng, Jiangtao,He, Hongwu,Hou, Leifeng,Jiang, Wen,Xie, Dan,Feng, Lingling,Cai, Meng,Peng, Hao
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p. 6491 - 6502
(2017/12/26)
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- A 4-N-substituted-5-chloriquine Trifluoromethylbiphenglyl compound and its preparation method and application
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The invention discloses a preparation method and biological activity of a compound with a function of resisting plant germs, 4-N-substituted-5-chloroquinazoline compound which is a compound represented by the general formulas (I) and (II) and a preparation method thereof. According to the invention, the 4-N-substituted-5-chloroquinazoline derivative is synthesized via three or five steps by adopting 2-amino-6-chlorobenzoic acid, formamide, phosphoryl chloride, concentrated hydrochloric acid, N-Boc piperazine and substituted benzyl chloride or benzyl bromine as raw materials and adopting sodium hydride, triethylamine and potassium carbonate as catalysts. The compounds I2, I4, I8 and II5 disclosed by the invention have relatively good inhibiting effects on plant fungi, and the compounds II1, II7, II10, II11, II16 and II17 show relatively high bacteriostatic activity on plant bacteria.
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Paragraph 0089; 0090; 0091
(2017/01/19)
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- Synthesis and SAR optimization of quinazolin-4(3H)-ones as poly(ADP-ribose)polymerase-1 inhibitors
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We have demonstrated that quinazolin-4(3H)-one, a nicotinamide (NI) mimic with PARP-1 inhibitory activity in the high micromolar range (IC50 = 5.75 μM) could be transformed into highly active derivatives with only marginal increase in molecular weight. Convenient one to two synthetic steps allowed us to explore extensive SAR at the 2-, and 5- through 8-positions of the quinazolin-4(3H)-one scaffold. Substitutions at the 2- and 8-positions were found to be most favorable for improved PARP-1 inhibition. The amino group at 8-position resulted in compound 22 with an IC50 value of 0.76 μM. Combination of the 8-amino substituent with an additional methyl substituent at the 2-position provided the most potent compound 31 [8-amino-2-methylquinazolin- 4(3H)-one, IC50 = 0.4 μM] in the present study. Compound 31 inhibited the proliferation of Brca1-deficient cells with an IC50 value of 49.0 μM and displayed >10-fold selectivity over wild type counterparts. Binding models of these derivatives within the active site of PARP-1 have further supported the SAR data and will be useful for future lead optimization efforts.
- Kulkarni, Shridhar S.,Singh, Satyakam,Shah, Janki R.,Low, Woon-Kai,Talele, Tanaji T.
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experimental part
p. 264 - 273
(2012/07/14)
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- Synthesis and antitumor evaluation of novel 5-substituted-4-hydroxy-8- nitroquinazolines as EGFR signaling-targeted inhibitors
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The synthesis and biological activity of a series of novel 5-substituted-4-hydroxy-8-nitroquinazolines that may function as inhibitors of EGFR- and/or ErbB-2-related oncogenic signaling are described. These compounds were prepared by SNAr reaction of 5-chloro-4-hydroxy-8- nitroquinazoline with alkyl or aryl amines, or alkyl alcohol as nucleophiles. Although the enzyme assay showed a weak inhibition effect against both EGFR and ErbB-2 tyrosine kinases, the cell-based antitumor activity turned out promising. Compounds having 5-anilino substituent exhibit high potency with 5-(4-methoxy)anilino-4-hydroxy-8-nitroquinazoline (1h) being the best dual EGFR/ErbB-2 inhibitors, which effectively inhibited the growth of both EGFR (MDA-MB-468, IC50 50 = 13 μM) overexpressing human tumor cell lines in vitro. More interestingly, the variation of the substituent(s) at the 3- and/or 4-position of the 5-anilino portion was found to modulate the selectivity and potency dramatically. However, compounds having an alkylamino or alkyloxy group at the 5-position of 4-hydroxy-8-nitroquinazolines are essentially inactive. These results are consistent with molecular modeling observations. This study was the first attempt to identify new structural types of dual EGFR/ErbB-2-related signaling inhibitors by incorporation of the anilino group at the 5-position of 4-hydroxy-8-nitroquinazolines' core structure, providing promising new templates for further development of potent inhibitors targeting both EGFR and ErbB-2 tyrosine kinases.
- Jin, Yi,Li, Hui-Yuan,Lin, Li-Ping,Tan, Jinzhi,Ding, Jian,Luo, Xiaomin,Long, Ya-Qiu
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p. 5613 - 5622
(2007/10/03)
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- Substituted isoquinolines and quinazolines as potential antiinflammatory agents. Synthesis and biological evaluation of inhibitors of tumor necrosis factor α
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A series of isoquinolin-1-ones and quinazolin-4-ones and related derivatives were prepared and evaluated for their ability to inhibit tumor necrosis factor α (TNFα) production in human peripheral blood monocytes stimulated with bacterial lipopolysaccharide (LPS). In an effort to optimize the TNFα inhibitory activity, a homologous series of N-alkanoic acid esters was prepared. Several electrophilic and nucleophilic substitutions were also carried out. Alkanoic acid esters of four carbons were found to be optimum for activity in both the isoquinoline and quinazoline series. Ring substituents such as fluoro, bromo, nitro, acetyl, and aminomethyl on the isoquinoline ring resulted in a significant loss of activity. Likewise, similar groups on the quinazoline ring also reduced inhibitory activity. However, the 6- and 7-aminoquinazoline derivatives, 75 and 76, were potent inhibitors, with IC50 values in the TNFα in vitro assay of approximately 5 μM for each. An in vivo mouse model of pulmonary inflammation was then used to evaluate promising candidate compounds identified in the primary in vitro assay. Compound 75 was selected for further study in this inhalation model, and was found to reduce the level of TNFα in brochoalveolar lavage fluid of LPS-treated mice by about 50% that of control mice. Thus, compounds such as 75, which can effectively inhibit proinflammatory cytokines such as TNFα in clinically relevant animal models of inflammation and fibrosis, may have potential as new antiinflammatory agents. Finally, a quinazoline derivative suitable to serve as a photoaffinity radiolabeled compound was prepared to help identify the putative cellular target(s) for these TNFα inhibitors.
- Chao, Qi,Deng, Lynn,Shih, Hsiencheng,Leoni, Lorenzo M.,Genini, Davide,Carson, Dennis A.,Cottam, Howard B.
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p. 3860 - 3873
(2007/10/03)
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