- Design and synthesis of novel artemisinin derivatives with potent activities against colorectal cancer in vitro and in vivo
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A series of novel derivatives of artemisinin-4-(arylamino)quinazoline have been designed and synthesized, and most of them showing potent in vitro cytotoxic activity against HCT116 and WM-266-4 cell lines. Compound 32 was the most active derivative against HCT116 cell line with an IC50 of 110 nM, and significantly improved the antitumor activity of the parent compounds dihydroartemisinin (DHA) (IC50 = 2.85 μM) and Gefitinib (IC50 = 19.82 μM). In vivo HCT116 xenografts assay showed that compound 32 exhibited potent antitumor activity with obvious tumor growth delay and tumor shrunken after 18 days treatment on xenografted mice, and especially without loss of body weight. Our results indicate that compounds 32 may represent a safe, novel structural lead for developing new chemotherapy of colorectal cancer.
- Wang, Liang-Liang,Kong, Lingmei,Liu, Hui,Zhang, Yunqin,Zhang, Li,Liu, Xingyong,Yuan, Feng,Li, Yan,Zuo, Zhili
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Read Online
- Design, synthesis, and evaluation of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as antitumor agents
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In our continuing search for novel small-molecule anticancer agents, we designed and synthesized a series of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5), focusing on the modification of substitution in the quinazolin-4(3H)-one moiety. The biological evaluation showed that all 13 designed and synthesized compounds displayed significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Structure–activity relationship analysis revealed that substitution of either electron-withdrawing or electron-releasing groups at positions 6 or 7 on the quinazolin-4(3H)-4-one moiety increased the cytotoxicity of the compounds, but substitution at position 6 seemed to be more favorable. In the caspase activation assay, compound 5l was found to activate the caspase activity by 291% in comparison to PAC-1, which was used as a control. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.
- Dung, Do T. M.,Park, Eun J.,Anh, Duong T.,Hai, Pham-The,Huy, Le D.,Jun, Hye W.,Kwon, Joo-Hee,Young Ji,Kang, Jong S.,Tung, Truong T.,Dung, Phan T. P.,Han, Sang-Bae,Nam, Nguyen-Hai
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- Photo-Triggered Self-Induced Homolytic Dechlorinative Sulfonylation/Cyclization of Unactivated Alkenes: Synthesis of Quinazolinones Containing a Sulfonyl Group
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A self-photocatalyzed sulfonylation/cyclization of quinazolinones containing unactivated alkenes with various sulfonyl chlorides was developed. The protocol provides access to sulfonyl radicals via energy transfer from the quinazolinone skeleton to the sulfonyl chloride. Notably, the transformations proceeded without any external photocatalysts, additives, or oxidants, providing an alternative method for fabricating sulfonylated compounds.
- Sun, Bin,Ding, Hao,Tian, Hai-Xia,Huang, Pan-Yi,Jin, Can,Wu, Chun-Lei,Shen, Run-Pu
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supporting information
p. 766 - 772
(2021/12/22)
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- Electrosynthesis of CF3-Substituted Polycyclic Quinazolinones via Cascade Trifluoromethylation/Cyclization of Unactivated Alkene
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An atom and step economy cascade trifluoromethylation/cyclization of unactivated alkene with Langlois reagent as a CF3 source is described. A variety of polycyclic quinazolinones were successfully synthesized in 52–81% yields under transition metal- and oxidant-free conditions. The Langlois reagent used in this strategy as a CF3 reagent possesses the advantages of bench-stablity, cost-effectivity and high-efficiency. Additionally, gram-scale reaction, broad substrate scope and good functional group tolerance demonstrated the synthetic usefulness of this protocol.
- He, Jiaying,Ling, Fei,Liu, Lei,Xu, Chao,Xu, Zhenhui,Yang, Zehui,Zhang, Wangqin,Zhong, Weihui
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supporting information
(2022/03/15)
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- Visible-Light Photosynthesis of CHF2/CClF2/CBrF2-Substituted Ring-fused Quinazolinones in Dimethyl Carbonate
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With eco-friendly and sustainable CO2-derived dimethyl carbonate as the sole solvent, the visible-light-induced cascade radical reactions have been established as a green and efficient tool for constructing various CHF2/CClF2/CBrF2-substituted ring-fused quinazolinones.
- Gui, Qing-Wen,He, Wei-Min,Huang, Wen-Jie,Lu, Zi-Qin,Ouyang, Wen-Tao,Teng, Fan,Xun, Changping,Yang, Hao,Zhu, Meng-Xue
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- Novel (Z)-N'-(2-oxoindolin-3-ylidene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides and an anticancer composition comprising the same as an active ingredient
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(Z)- N' - (2-oxoindolin -3 - ylidene) -2 - (4-oxoquinazolin -3 (4H) - yl) acetohydrazide and an anticancer composition containing the same as an active ingredient. , It will be described below. (Z)- N' - (2-oxoindoline -3 - ylidene) -2 - (4-oxazoline -3 (4H) - yl) acetohydrazide according to the present invention activates procacaspase -3 to promote the conversion to caspase -3, so that it can be used as a proliferation inhibitor for various cancer cells. The compound according to the present invention can be developed as an active ingredient of a potent anticancer agent.
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Paragraph 0097
(2021/05/18)
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- Self-catalyzed phototandem perfluoroalkylation/cyclization of unactivated alkenes: Synthesis of perfluoroalkyl-substituted quinazolinones
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A novel visible-light-induced radical tandem trifluoromethylation/cyclization of unactivated alkenes with sodium perfluoroalkanesulfinates (Rf = CF3, C3F7, C4F9, C6F13, C8F17) under air atmosphere has been developed. A range of quinazolinones containing unactivated alkene moiety and sodium perfluoroalkanesulfinates were compatible with this transformation, leading to a variety of perfluoroalkyl-substituted quinazoline alkaloids. Remarkably, the experiment can be carried out without any metal catalyst, strong oxidant, or external photosensitizer.
- Sun, Bin,Huang, Panyi,Yan, Zhiyang,Shi, Xiayue,Tang, Xiaoli,Yang, Jin,Jin, Can
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supporting information
p. 1026 - 1031
(2021/02/06)
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- Photoinduced homolytic decarboxylative acylation/cyclization of unactivated alkenes with α-keto acid under external oxidant and photocatalyst free conditions: access to quinazolinone derivatives
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A novel and green strategy for the synthesis of acylated quinazolinone derivativesviaphoto-induced decarboxylative cascade radical acylation/cyclization of quinazolinone bearing unactivated alkenes has been developed. The protocol provides a novel route to access acyl radicals from α-keto acids through a self-catalyzed energy transfer process. Most importantly, the reaction proceeded smoothly without any external photocatalyst, additive or oxidant, and could be easily scaled-up in flow conditions with sunlight irradiation.
- Sun, Bin,Shi, Rongcheng,Zhang, Kesheng,Tang, Xiaoli,Shi, Xiayue,Xu, Jiayun,Yang, Jin,Jin, Can
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supporting information
p. 6050 - 6053
(2021/06/21)
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- Photo-triggered self-catalyzed fluoroalkylation/cyclization of unactivated alkenes: Synthesis of quinazolinones containing the CF2R group
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A novel photo-triggered self-catalyzed fluoroalkylation/cyclization of quinazolinones containing unactivated alkenes with various fluoroalkyl bromides has been developed. This transformation exhibits excellent substrate generality with respect to both the coupling partners. Of note is that this is the first example describing the Csp3-Br bond homolysis of alkyl bromides via a substrate (quinazolinones) induced energy transfer process. Additionally, the mild conditions, tolerance to a wide range of functional groups and operational simplicity make this protocol practical for the synthesis of fluorine-containing ring-fused quinazolinones. This journal is
- Yang, Jin,Sun, Bin,Ding, Hao,Huang, Pan-Yi,Tang, Xiao-Li,Shi, Rong-Cheng,Yan, Zhi-Yang,Yu, Chuan-Ming,Jin, Can
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supporting information
p. 575 - 581
(2021/01/28)
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- Synthesis, Anti-Tomato Spotted Wilt Virus Activities, and Interaction Mechanisms of Novel Dithioacetal Derivatives Containing a 4(3 H)-Quinazolinone Pyrimidine Ring
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A series of unreported novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring were synthesized, and their antiviral activities were evaluated against tomato spotted wilt virus (TSWV). A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was established, and compound D32 was designed and synthesized according to the analysis results of the CoMFA and CoMSIA models. The bioassay results showed that compound D32 exhibited excellent inactivation activity against TSWV, with EC50 values of 144 μg/mL, which was better than those of ningnanmycin (149 μg/mL) and the lead compound xiangcaoliusuobingmi (525 μg/mL). The binding ability of compound D32 to TSWV CP was tested by microscale thermophoresis (MST), and the binding constant value was 4.4 μM, which was better than those of ningnanmycin (6.2 μM) and xiangcaoliusuobingmi (59.1 μM). Therefore, this study indicates that novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring may be applied as new antiviral agents.
- Chen, Jixiang,Hu, Deyu,Song, Baoan,Zu, Guangcheng
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p. 14459 - 14466
(2021/12/06)
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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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- 6-Nitro-Quinazolin?4(3H)?one Exhibits Photodynamic Effects and Photodegrades Human Melanoma Cell Lines. A Study on the Photoreactivity of Simple Quinazolin?4(3H)?ones
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Photochemo and photodynamic therapies are minimally invasive approaches for the treatment of cancers and powerful weapons for competing bacterial resistance to antibiotics. Synthetic and naturally occurring quinazolinones are considered privileged anticancer and antibacterial agents, with several of them to have emerged as commercially available drugs. In the present study, applying a single-step green microwave irradiation mediated protocol we have synthesized eleven quinazolinon?4(3H)?ones, from cheap readily available anthranilic acids, in very good yields and purity. These products were irradiated in the presence of pBR322 plasmid DNA under UVB, UVA and visible light. Four of the compounds proved to be very effective DNA photocleavers, at low concentrations, being time and concentration dependent as well as pH independent. Participation of reactive oxygen species was related to the substitution of quinazolinone derivatives. 6-Nitro-quinazolinone in combination with UVA irradiation was found to be in vitro photodestructive for three cell lines; glioblastoma (U87MG and T98G) and mainly melanoma (A?375). Thus, certain appropriately substituted quinazolinones may serve as new lead photosensitizers for the development of promising biotechnological applications and as novel photochemo and photodynamic therapeutics.
- Panagopoulos, Anastasios,Balalas, Thomas,Mitrakas, Achilleas,Vrazas, Vassilios,Katsani, Katerina R.,Koumbis, Alexandros E.,Koukourakis, Michael I.,Litinas, Konstantinos E.,Fylaktakidou, Konstantina C.
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p. 826 - 836
(2021/02/03)
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- Cobalt-Catalyzed Tandem Transformation of 2-Aminobenzonitriles to Quinazolinones Using Hydration and Dehydrogenative Coupling Strategy
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A tandem synthesis of quinazolinones from 2-aminobenzonitriles is demonstrated here by using an aliphatic alcohol-water system. For this transformation, a cheap and easily available cobalt salt and P(CH2CH2PPh2)3 (PP3) ligand were employed. The substrate scope, scalability, and synthesis of natural products exhibited the vitality of this protocol.
- Samim, Sk. Abdus,Roy, Bivas Chandra,Nayak, Sourav,Kundu, Sabuj
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p. 11359 - 11367
(2020/10/12)
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- New Acetohydrazides Incorporating 2-Oxoindoline and 4-Oxoquinazoline: Synthesis and Evaluation of Cytotoxicity and Caspase Activation Activity
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In our search for new small molecules activating procaspase-3, we have designed and synthesized a series of new acetohydrazides incorporating both 2-oxoindoline and 4-oxoquinazoline scaffolds. Biological evaluation showed that a number of these acetohydrazides were comparably or even more cytotoxic against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI?H23, lung cancer) in comparison to PAC-1, a first procaspase-3 activating compound, which was used as a positive control. One of those new compounds, 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N′-[(3Z)-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetohydrazide activated the caspase-3 activity in U937 human lymphoma cells by 5-fold higher than the untreated control. Three of the new compounds significantly induced necrosis and apoptosis in U937 cells.
- Anh, Duong Tien,Duc, Phan Huy,Duc-Anh, Lai,Hai, Pham-The,Han, Sang-Bae,Huan, Le Cong,Huong, Le-Thi-Thu,Kang, Jong Soon,Kim Oanh, Dao Thi,Lee, Hye Jin,Nam, Nguyen-Hai,Park, Eun Jae,Thanh Hai, Dinh Thi,Tran, Phuong-Thao,Truong, Bui Xuan
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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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- Commercial Copper-Catalyzed Aerobic Oxidative Synthesis of Quinazolinones from 2-Aminobenzamide and Methanol
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The focus of this study was the development of a new synthetic method for quinazolinones based on the principles of Green Chemistry. Quinazolinones were synthesized from 2-aminobenzamide using methanol as both the C1 source and a green solvent in the presence of base Cs2CO3. Additionally, a commercially available, economical copper complex was used as a catalyst in the reaction. The desired products were achieved in moderate to high yield with up to 99 % isolated yield.
- Chatwichien, Jaruwan,Choommongkol, Vachira,Kerdphon, Sutthichat,Meepowpan, Puttinan,Rithchumpon, Puracheth,Sanghong, Patthadon,Singh, Thishana
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supporting information
p. 2730 - 2734
(2020/05/18)
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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; 69
(2019/10/01)
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- Novel N-Hydroxybenzamides or N-Hydroxypropenamides Incorporating Quinazolin-4(3H)-ones as Histone Deacetylase Inhibitors and Anticancer Composition Comprising the Same
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The present invention relates to novel N-hydroxy benzamides or N-hydroxy propenamides based on quinazoline-4(3H)-ones as histone deacetylase (HDAC) inhibitors and a use thereof. More specifically, a compound according to the present invention has a strong HDAC inhibitory activity, thereby being able to be used as proliferation inhibitors for various cancer cells. Therefore, the compound according to the invention is expected to be able to be developed as an active component of strong anti-cancer drugs.COPYRIGHT KIPO 2019
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Paragraph 0135; 0136
(2019/05/15)
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- Novel Hydroxamic Acid Incorporating Quinazolin-4(3H)-ones as Histone Deacetylase Inhibitors and Anticancer Composition Comprising the Same
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The compound according HDAC(histone deacetylase) to the present -4(3H)- won invention can, be used as an active. ingredient of, a potent anticancer agent, HDAC since the compound according, to the present invention can be used. as, an active ingredient of a potent anticancer agent, since the compound. according to the present invention can be used as an active ingredient of a potent anticancer agent. (by machine translation)
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Paragraph 0105-0106
(2020/03/03)
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- (E)-N'-Arylidene-2-(4-oxoquinazolin-4(3H)-yl) acetohydrazides: Synthesis and evaluation of antitumor cytotoxicity and caspase activation activity
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In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-ones (5, 6, 7). Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU. Analysis of structure-activity relationships showed that the introduction of different substituents at C-6 position on the quinazolin-4(3H)-4-one moiety, such as 6-chloro or 6-methoxy potentially increased the cytotoxicity of the compounds. In term of caspase activation activity, several compounds were found to exhibit potent effects, (e.g. compounds 7 b, 5n, and 5l). Especially, compound 7 b activated caspases activity by almost 200% in comparison to that of PAC-1. Further docking simulation also revealed that this compound potentially is a potent allosteric inhibitor of procaspase-3.
- Huan, Le Cong,Phuong, Cao Viet,Truc, Le Cong,Thanh, Vo Nguyen,Pham-The, Hai,Huong, Le-Thi-Thu,Thuan, Nguyen Thi,Park, Eun Jae,Ji, A Young,Kang, Jong Soon,Han, Sang-Bae,Tran, Phuong-Thao,Nam, Nguyen-Hai
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p. 465 - 478
(2019/01/26)
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- Quinazolin-4(3H)-one-Based Hydroxamic Acids: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
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The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin-4(3H)-ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI?H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N-hydroxy-7-(7-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5b) and N-hydroxy-7-(6-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5c) (IC50 values, 0.10–0.16 μm) were found to be approximately 30-fold more cytotoxic than SAHA (IC50 values of 3.29–3.67 μm). N-Hydroxy-7-(4-oxoquinazolin-3(4H)-yl)heptanamide (5a; IC50 values of 0.21–0.38 μm) was approximately 10- to 15-fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC50 values in sub-micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c, strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.
- Hieu, Doan Thanh,Anh, Duong Tien,Hai, Pham-The,Thuan, Nguyen Thi,Huong, Le-Thi-Thu,Park, Eun Jae,Young Ji,Soon Kang, Jong,Phuong Dung, Phan Thi,Han, Sang-Bae,Nam, Nguyen-Hai
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- Novel 3,4-dihydro-4-oxoquinazoline-based acetohydrazides: Design, synthesis and evaluation of antitumor cytotoxicity and caspase activation activity
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In search for novel small molecules with antitumor cytotoxicity via activating procaspase-3, we have designed and synthesized three series of novel (E)-N′-benzylidene-4-oxoquinazolin-3(4H)-yl)acetohydrazides (5a-j, 6a-h, and 7a-h). On the phenyl ring ò the benzylidene part, three different substituents, including 2-OH-4-OCH3, 4-OCH3, and 4-N(CH3)2, were introduced, respectively. Biological evaluation showed that the acetohydrazides in series 5a-j, in which the phenyl ring of the benzylidene part was substituted by 2-OH-4-OCH3 substituent, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). Most of the compounds, in this series, especially compounds 5c, 5b and 5h, also significantly activated caspase-3 activity. Among these, compound 5c displayed 1.61-fold more potent than PAC-1 as caspase-3 activator. Cell cycle analysis showed that compounds 5b, 5c, and 5h significantly arrested the cell cycle in G1 phase. Further apoptotic studies also demonstrated compounds 5b, 5c, and 5h as strong apoptotic cell death inducers. The docking simulation studies showed that these compounds could activate procaspase via chelating Zn2+ ion bound to the allosteric site of the zymogen.
- Huan, Le Cong,Tran, Phuong-Thao,Phuong, Cao Viet,Duc, Phan Huy,Anh, Duong Tien,Hai, Pham The,Huong, Le Thi Thu,Thuan, Nguyen Thi,Lee, Hye Jin,Park, Eun Jae,Kang, Jong Soon,Linh, Nguyen Phuong,Hieu, Tran Trung,Oanh, Dao Thi Kim,Han, Sang-Bae,Nam, Nguyen-Hai
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- Quinazoline-Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
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In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N-hydroxybenzamides incorporating quinazoline heterocycles (4a?–?4i, 6a?–?6i). Bioevaluation showed that these quinazoline-based hydroxamic acids and N-hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). In term of cytotoxicity, several compounds, e.g., 4g, 4c, 4g?–?4i, 6c, and 6h, displayed from 5- up to 10-fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat). The compounds were also generally comparable to SAHA in inhibiting HDACs with IC50 values in sub-micromolar range. Some compounds, e.g., 4g, 6c, 6e, and 6h, were even more potent HDAC inhibitors compared to SAHA in HeLa extract assay. Docking studies demonstrated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities higher than that of SAHA. Detailed investigation on the estimation of absorption, distribution, metabolism, excretion, and toxicity (ADMET) suggested that compounds 4g, 6c, and 6g, while showing potent HDAC2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates.
- Hieu, Doan Thanh,Anh, Duong Tien,Hai, Pham-The,Huong, Le-Thi-Thu,Park, Eun Jae,Choi, Jeong Eun,Kang, Jong Soon,Dung, Phan Thi Phuong,Han, Sang-Bae,Nam, Nguyen-Hai
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- Structure-metabolism relationships in human-AOX: Chemical insights from a large database of aza-aromatic and amide compounds
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Aldehyde oxidase (AOX) is a metabolic enzyme catalyzing the oxidation of aldehyde and aza-aromatic compounds and the hydrolysis of amides, moieties frequently shared by the majority of drugs. Despite its key role in human metabolism, to date only fragmentary information about the chemical features responsible for AOX susceptibility are reported and only "very local" structure-metabolism relationships based on a small number of similar compounds have been developed. This study reports a more comprehensive coverage of the chemical space of structures with a high risk of AOX phase I metabolism in humans. More than 270 compounds were studied to identify the site of metabolism and themetabolite(s). Both electronic [supported by density functional theory (DFT) calculations] and exposure effects were considered when rationalizing the structure-metabolism relationship.
- Lepri, Susan,Ceccarelli, Martina,Milani, Nicolò,Tortorella, Sara,Cucco, Andrea,Valeri, Aurora,Goracci, Laura,Brink, Andreas,Cruciani, Gabriele
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p. E3178 - E3187
(2017/04/24)
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- Method of synthesizing quinazolinone derivative by using methanol as raw material
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The invention discloses a method of synthesizing a quinazolinone derivative by using methanol as a raw material. The method comprises adding an anthranilamide derivative II, methanol III and an iridium metal complex in a reaction container; performing a reaction on the reaction mixture in a microwave reactor or under magnetic stirring at a temperature of 130 +/- 10 DEG C for 2 hours or more; performing cooling to a room temperature; removing a solvent in a spin drying manner; and performing column separation to obtain a target compound. The method provided by the invention adopts nontoxic and renewable methanol as a raw material, and the by-products in the reaction are hydrogen gas and water, thus the method does not pollute the environment and meet the requirements of green chemistry, so that the method has a wide development prospect.
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Paragraph 0035; 0036; 0037; 0038
(2017/12/06)
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- A microwave catalysis in the aqueous phase a method of preparing Quinazolinone compounds
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The invention discloses a method for preparing quinazolinone in water phase through microwave catalysis. The method comprises the step: by utilizing a water-soluble coordination compound (such as 8-hydroxyquinoline) as a catalyst, carrying out high-efficiency microwave catalysis on the reaction of 2-halogenated benzaldehyde and amidine salts in pure water phase. The invention relates to a method for preparing a quinazolinone compound, which is environment-friendly, simple and convenient to operate, safe and low-cost, and high-efficiency. Compared with the prior art, the method not only can be applicable to a great deal of functional groups, high in yield, fewer in side products, but also is simple and safe to operate, low in cost, and environment-friendly.
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Paragraph 0039
(2017/02/09)
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- Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity
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There has been significant interest in developing a transient receptor potential A1 (TRPA1) antagonist for the treatment of pain due to a wealth of data implicating its role in pain pathways. Despite this, identification of a potent small molecule tool possessing pharmacokinetic properties allowing for robust in vivo target coverage has been challenging. Here we describe the optimization of a potent, selective series of quinazolinone-based TRPA1 antagonists. High-throughput screening identified 4, which possessed promising potency and selectivity. A strategy focused on optimizing potency while increasing polarity in order to improve intrinisic clearance culminated with the discovery of purinone 27 (AM-0902), which is a potent, selective antagonist of TRPA1 with pharmacokinetic properties allowing for >30-fold coverage of the rat TRPA1 IC50 in vivo. Compound 27 demonstrated dose-dependent inhibition of AITC-induced flinching in rats, validating its utility as a tool for interrogating the role of TRPA1 in in vivo pain models.
- Schenkel, Laurie B.,Olivieri, Philip R.,Boezio, Alessandro A.,Deak, Holly L.,Emkey, Renee,Graceffa, Russell F.,Gunaydin, Hakan,Guzman-Perez, Angel,Lee, Josie H.,Teffera, Yohannes,Wang, Weiya,Youngblood, Beth D.,Yu, Violeta L.,Zhang, Maosheng,Gavva, Narender R.,Lehto, Sonya G.,Geuns-Meyer, Stephanie
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p. 2794 - 2809
(2016/04/10)
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- PIPERIDINE SUBSTITUTED TRICYCLIC PYRAZOLO[1,5-A]PYRIMIDINE DERIVATIVES WITH INHIBITORY ACTIVITY ON THE REPLICATION OF THE RESPIRATORY SYNCYTIAL VIRUS (RSV)
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The invention concerns novel substituted tricyclic pyrazolo pyrimidine compounds of formula (I-a) or (I-b) having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns the preparation of such novel compounds, compositions comprising these compounds, and the compounds for use in the treatment of respiratory syncytial virus infection.
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Page/Page column 20; 21
(2016/06/28)
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- PIPERIDINE SUBSTITUTED PYRAZOLO[1,5-A]PYRIMIDINE DERIVATIVES WITH INHIBITORY ACTIVITY ON THE REPLICATION OF THE RESPIRATORY SYNCYTIAL VIRUS (RSV)
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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
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Page/Page column 23; 24
(2016/11/07)
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- Acceptorless Dehydrogenative Coupling of o-Aminobenzamides with the Activation of Methanol as a C1 Source for the Construction of Quinazolinones
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A strategy for the synthesis of quinazolinones via acceptorless coupling of o-aminobenzamides with methanol has been accomplished in the presence of the metal-ligand bifunctional catalyst [Cp?Ir(2,2′-bpyO)(H2O)]. Notably, this research exhibited the potential of transition-metal-catalyzed activation of methanol as a C1 source for the construction of heterocycles.
- Li, Feng,Lu, Lei,Liu, Pengcheng
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supporting information
p. 2580 - 2583
(2016/06/15)
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- Thieno[2,3-d]pyrimidine-2-carboxamides bearing a carboxybenzene group at 5-position: Highly potent, selective, and orally available MMP-13 inhibitors interacting with the S1″ binding site
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On the basis of X-ray co-crystal structures of matrix metalloproteinase-13 (MMP-13) in complex with its inhibitors, our structure-based drug design (SBDD) strategy was directed to achieving high affinity through optimal protein-ligand interaction with the unique S1″ hydrophobic specificity pocket. This report details the optimization of lead compound 44 to highly potent and selective MMP-13 inhibitors based on fused pyrimidine scaffolds represented by the thienopyrimidin-4-one 26c. Furthermore, we have examined the release of collagen fragments from bovine nasal cartilage in response to a combination of IL-1 and oncostatin M.
- Nara, Hiroshi,Sato, Kenjiro,Naito, Takako,Mototani, Hideyuki,Oki, Hideyuki,Yamamoto, Yoshio,Kuno, Haruhiko,Santou, Takashi,Kanzaki, Naoyuki,Terauchi, Jun,Uchikawa, Osamu,Kori, Masakuni
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supporting information
p. 5487 - 5505
(2014/12/11)
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- Synthesis and antiviral bioactivity of novel (1E, 4E)-1-aryl-5-(2- (quinazolin-4-yloxy)phenyl)-1,4-pentadien-3-one derivatives
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A series of novel (1E, 4E)-1-aryl-5-[2-(quinazolin-4-yloxy)phenyl]-1,4- pentadien-3-one derivatives were designed and synthesized by reacting substituent aldehyde with intermediates 4a-f. Antiviral bioassays indicated that most of the compounds exhibited promising ex vivo antiviral bioactivities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) at 500 μg/mL. The relationship between structure and antiviral activity was also discussed. Compounds 5a, 6e, and 6g could possess appreciable protective bioactivities on TMV ex vivo by approximately 50% (EC50) at 257.7, 320.7 and 243.3 μg/mL. This study is the first to demonstrate that (1E, 4E)-1-aryl-5-(2-(quinazolin-4-yloxy)phenyl)-1,4-pentadien-3-one can be used to develop potential virucides for plants.
- Luo, Hui,Liu, Jiaju,Jin, Linhong,Hu, Deyu,Chen, Zhen,Yang, Song,Wu, Jian,Song, Baoan
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supporting information
p. 662 - 669
(2013/07/25)
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- Novel dithiocarbamic acid esters derived from 6-aminomethyl-4- anilinoquinazolines and 6-aminomethyl-4-anilino-3-cyanoquinolines as potent EGFR inhibitors
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Two series of dithiocarbamic acid esters, 4-anilinoquinazoline-6- ylmethylcarbamodithioic acid esters and 3-cyano-4-anilinoquinolin-6- ylmethylcarbamodithioic acid esters, were designed and synthesized. The effect of the synthesized compounds on cell proliferation was evaluated by MTT assay against three human cancer cell lines: MDA-MB-468, SK-BR-3 and HCT-116. Most of the compounds are equally or more potent than the positive control lapatinib. Three compounds (14d, 14h and 14i) were identified as dual inhibitors of the EGFR and ErbB-2 kinases and two compounds (14b and 14c) were identified as multi-target kinase inhibitors, and they are very worthy of further study. Installation of the dithiocarbamic acid ester group at the 6-position of 4-anilinoquinazoline or 3-cyano-4-anilinoquinoline could improve the inhibitory activity. Different dithiocarbamic acid ester groups significantly affect the activities. Two series of dithiocarbamic acid esters were designed and synthesized. Compound 14d was found to have higher biological activity than lapatinib. Some useful structure-activity relationships were revealed. Copyright
- Zhang, Xin,Li, Ridong,Qiao, Kang,Ge, Zemei,Zhang, Liangren,Cheng, Tieming,Li, Runtao
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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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- Design and synthesis of antifungal benzoheterocyclic derivatives by scaffold hopping
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The incidence of invasive fungal infections and associated mortality is increasing dramatically. Although azoles are first-line antifungal agents, cross-resistance and hepatic toxicity are their two major limitations. The discovery of novel non-azole lead compounds will be helpful to overcome these problems. On the basis of our previously reported benzopyran non-azole CYP51 inhibitor, scaffold hopping was used to design structurally diverse new compounds and expand the structure-activity relationships of the lead structure. Five kinds of scaffolds, namely benzimidazole, benzoxazole, benzothiazole, quinazolin-4-one and carboline, were chosen for synthesis. In vitro antifungal activity data and results from molecular docking revealed that the scaffold was important for the antifungal activity. Several compounds showed potent activity against both standard and clinically resistant fungal pathogens, suggesting that they can serve as a good starting point for the discovery of novel antifungal agents.
- Sheng, Chunquan,Che, Xiaoying,Wang, Wenya,Wang, Shengzheng,Cao, Yongbing,Yao, Jianzhong,Miao, Zhenyuan,Zhang, Wannian
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scheme or table
p. 1706 - 1712
(2011/05/06)
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- QUINAZOLINE DERIVATIVES AS RAF KINASE MODULATORS AND METHODS OF USE THEREOF
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Compounds according to formula (I), compositions and methods are provided for modulating the activity of RAF kinases, including BRAF kinase and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by RAF kinases. Formula (I): or a pharmaceutically acceptable salt, solvate, clathrate of hydrate thereof, wherein X is O or S(O)t; Ra is O or S.
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Page/Page column 170
(2009/10/22)
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- Novel series of 8H-quinazolino[4,3-b]quinazolin-8-ones via two Niementowski condensations
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Efficient microwave-assisted multi-step synthesis of 8H-quinazolino[4,3-b]quinazolin-8-one was investigated. The synthesis involved two Niementowski condensations from anthranilic acids. Homogeneous or heterogeneous conditions were studied with the aim to develop convenient syntheses of the desired compounds.
- Alexandre, Fran?ois-René,Berecibar, Amaya,Wrigglesworth, Roger,Besson, Thierry
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p. 1413 - 1419
(2007/10/03)
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- Discovery of quinazolines as a novel structural class of potent inhibitors of NF-κB activation
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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
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p. 383 - 391
(2007/10/03)
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- Microwave-assisted Niementowski reaction. Back to the roots
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In a search to speed up an aspect of the drug discovery processes, the Niementowski synthesis of the 3H-quinazolin-4-one core was reinvestigated using microwave irradiation. The experimental methodology and microwave conditions described here are well established, allowing significant rate enhancements and good yields compared to conventional reaction conditions.
- Alexandre, Fran?ois-René,Berecibar, Amaya,Besson, Thierry
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p. 3911 - 3913
(2007/10/03)
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- Sulfonic acid sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds
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The compounds of formula I herein exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, for treating a patient suffering from, or subject to, a physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.
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- Structure-activity relationships of quinazoline derivatives: Dual-acting compounds with inhibitory activities toward both TNF-α production and T cell proliferation
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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
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p. 545 - 548
(2007/10/03)
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- Tyrphostins IV - Highly potent inhibitors of EGF receptor kinase. Structure-activity relationship study of 4-anilidoquinazolines
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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
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p. 1203 - 1207
(2007/10/03)
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- Anti-cancer quinazoline derivatives
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A compound of formula I: STR1 wherein R is hydrogen; oran alkyl, alkenyl or alkynyl group of up to 6 carbon atoms; nis O; 1 or 2; Z represents --CH=CH-- or --S--; each X independently represents halogeno, C1 -C4 alkyl, C1 -C4 alkoxy, nitro or trifluoromethyl; and Y represents a group of formula: STR2 or a pharmaceutically acceptable salt or ester thereof.
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- Quinazoline antifolates inhibiting thymidylate synthase: 2-Desamino derivatives with enhanced solubility and potency
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The poor solubility of the thymidylate synthase (TS) inhibiting antifolate 10-propargyl-5,8-dideazafolic acid has posed problems for its clinical use and is probably responsible for its renal toxicity. The insolubility is caused by the 2-amino-3,4-dihydro-4-oxopyridimine moiety of the drug which stabilizes the solid state by intermolecular hydrogen bonding. In examining this moiety we have removed the 2-amino group and now report on 2-desamino-10-propargyl-5,8-dideazafolic acid (8e) and four analogues with H, Me, Et, and allyl at N10. 3,4-Dihydro-4-oxo-6-methylquinazoline was solubilized by alkylating the lactam nitrogen with chloromethyl pivalate. Reaction with N-bromosuccinimide gave the corresponding 6-bromomethyl compound, which was coupled with diethyl N-(4-aminobenzoyl)-L-glutamate or the appropriate N-substituted derivative thereof. The quinazoline N3 nitrogen and carboxyl groups in the product were simultaneously deprotected by cold alkali in the final step to give the desired five antifolates. These were tested against L1210 TS and its was found that removal of the 2-amino group caused a slight (3-9-fold) loss of TS inhibition. 8e was only 8-fold a lesser TS inhibitor than the parent drug. Inhibition of rat liver dihydrofolate reductase was reduced by over 1 order of magnitude for three compounds tested. All five analogues were more cytotoxic to L1210 cells in culture than their 2-amino counterparts; 8e was 8.5-fold more active with an ID50 of 0.4 μM. This remarkable result probably owes to increased cellular penetration. 8e was 5-fold more soluble than 1 at pH 5.0 and > 340-fold more soluble at pH 7.4.
- Jones,Thornton,Flinn,Jackman,Newell,Calvert
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p. 847 - 852
(2007/10/02)
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- Defined Dimensional Alterations in Enzyme Substrates. General Synthetic Methodology for the Bent Dihydro-lin-benzopurines
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The use of cycloaddition reactions for the synthesis of partially reduced heterocyclic systems has been shown to be an attractive approach to dihydrobenzimidazoles, dihydroquinazolines, and dihydro-lin-benzopurines.The first representatives of the bent dihydro-lin-benzopurines to be synthesized were 4,9-dihydroimidazo-quinazoline-2,8-(1H,7H)-dione (20) and 4,9-dihydro-lin-benzouric acid (21).
- Stevenson, Thomas M.,Kazmierczak, Franciszek,Leonard, Nelson J.
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p. 616 - 620
(2007/10/02)
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- THE REACTIONS OF ORTHO AMINOBENZOIC ACIDS WITH GOLD'S REAGENT: A TWO ATOM LYNCH PIN TRANSFORMATION
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A series of ortho aminobenzoic acids were treated with Gold's reagent.In each case a 4-hydroxyquinazoline was produced.The resulting transformation constitutes the use of Gold's reagent as a two atom lynch pin.
- Gupton, John T.,Correia, Keith F.,Hertel, George R.
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p. 1013 - 1026
(2007/10/02)
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