- Design, synthesis, and evaluation of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as antitumor agents
-
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
-
-
- 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)
-
- Self-catalyzed phototandem perfluoroalkylation/cyclization of unactivated alkenes: Synthesis of perfluoroalkyl-substituted quinazolinones
-
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
-
supporting information
p. 1026 - 1031
(2021/02/06)
-
- Visible-Light-Induced Radical Difluoromethylation/Cyclization of Unactivated Alkenes: Access to CF2H-Substituted Quinazolinones
-
A mild and efficient visible-light-induced radical difluoromethylation/cyclization of unactivated alkenes toward the synthesis of substituted quinazolinones with easily accessible difluoromethyltriphenylphosphonium bromide has been developed. The transformation has the advantages of wide functional group compatibility, a broad substrate scope, and operational simplicity. The benign protocol offers a facile access to pharmaceutically valuable difluoromethylated polycyclic quinazolinones.
- Chen, Xiaoyu,Liu, Bo,Pei, Congcong,Li, Jingya,Zou, Dapeng,Wu, Yangjie,Wu, Yusheng
-
supporting information
p. 7787 - 7791
(2021/10/20)
-
- Synthesis and evaluation of new 4(3H)-Quinazolinone derivatives as potential anticancer agents
-
A series of new 4(3H)-quinazolinones were synthesized and evaluated for their cytotoxic activity against a set of human cancer cell lines MDA-MB-231 and MCF-7 (breast), HCT-116 and HT-29 (colon) and A549 (lung). Among the tested compounds, 22a exhibited p
- Gatadi, Srikanth,Pulivendala, Gauthami,Gour, Jitendra,Malasala, Satyaveni,Bujji, Sushmitha,Parupalli, Ramulu,Shaikh, Mujahid,Godugu, Chandraiah,Nanduri, Srinivas
-
-
- Visible-light induced copper(i)-catalyzed oxidative cyclization of: O -aminobenzamides with methanol and ethanol via HAT
-
The use of the in situ generated ligand-copper superoxo complex absorbing light energy to activate the alpha C(sp3)-H of MeOH and EtOH via the hydrogen atom transfer (HAT) process for the synthesis of quinazolinones by oxidative cyclization of alcohols with o-aminobenzamide has been investigated. The synthetic utility of this protocol offers an efficient synthesis of a quinazolinone intermediate for erlotinb (anti-cancer agent) and 30 examples were reported.
- Bhargava Reddy, Mandapati,Prasanth, Kesavan,Anandhan, Ramasamy
-
supporting information
p. 9601 - 9605
(2020/12/28)
-
- A in ammonia water condition of microwave halo benzoic acid synthesis method of the quinazoline compounds
-
The invention discloses a in ammonia water condition of microwave halo benzoic acid synthetic quinazoline compounds of the method, the use of palladium chloride to serve as the catalyst, in ammonia water under the microwave heating condition, neighbouring halogen benzoic acid generated by the reaction with the isocyanate of the quinazoline compounds of the method, the invention an environment-friendly, the operation is simple, cheap and safe, efficient process for producing quinazoline compounds of the method. Compared with the prior art, this method not only can be applied to a large number of functional groups, the productive rate is high, few by-products, and the operation is simple, safe, low cost, environmental protection.
- -
-
Paragraph 0017; 0038
(2019/02/13)
-
- A in the aqueous phase under microwave conditions using halogenated benzamide fast synthesis of quinazoline compounds of the method
-
The invention discloses a in the aqueous phase under microwave conditions using halogenated benzamide fast synthesis of quinazoline compounds of the method, the use of palladium chloride to serve as the catalyst, in water under microwave heating conditions, neighbouring halogen benzamide with an isocyanate reaction to produce the quinazoline compounds of the method, the invention an environment-friendly, the operation is simple, cheap and safe, efficient process for producing quinazoline compounds of the method. Compared with the prior art, this method not only can be applied to a large number of functional groups, the productive rate is high, few by-products, and the operation is simple, safe, low cost, environmental protection.
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Paragraph 0015; 0036
(2019/02/13)
-
- Novel Hydroxamic Acid Incorporating Quinazolin-4(3H)-ones as Histone Deacetylase Inhibitors and Anticancer Composition Comprising the Same
-
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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- Quinazolin-4(3H)-one-Based Hydroxamic Acids: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
-
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
-
-
- Novel 3,4-dihydro-4-oxoquinazoline-based acetohydrazides: Design, synthesis and evaluation of antitumor cytotoxicity and caspase activation activity
-
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
-
-
- As neuroprotective agents of pharmaceutical compounds
-
The invention discloses a medicinal compound as a neuroprotective agent. The medicinal compound is a neuronal nitric oxide synthase-postsynaptic density protein 95 (nNOS-PSD95) decoupling agent. The medicinal compound is a benzene ring derivative shown in the general formula (I) or its pharmaceutically acceptable salt. The invention further discloses a preparation method of the medicinal compound and a use of the medicinal compound in prevention and treatment on neuronal damage influence-caused diseases.
- -
-
Paragraph 0841; 0842; 0843; 0844
(2019/06/26)
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- A Novel Conjugate of Bis[((4-bromophenyl)amino)quinazoline], a EGFR-TK Ligand, with a Fluorescent Ru(II)-Bipyridine Complex Exhibits Specific Subcellular Localization in Mitochondria
-
The epidermal growth factor receptor (EGFR) is a key target in anticancer research, whose aberrant function in malignancies has been linked to severe irregularities in critical cellular processes, including cell cycle progression, proliferation, differentiation, and survival. EGFR mutant variants, either transmembrane or translocated to the mitochondria and/or the nucleus, often exhibit resistance to EGFR inhibitors. The ability to noninvasively image and quantify EGFR provides novel approaches in the detection, monitoring, and treatment of EGFR-related malignancies. The current study aimed to deliver a new theranostic agent that combines fluorescence imaging properties with EGFR inhibition. This was achieved via conjugation of an in-house-developed ((4-bromophenyl)amino)quinazoline inhibitor of mutant EGFR-TK, selected from a focused aminoquinazoline library, with a [Ru(bipyridine)3]2+ fluorophore. A triethyleneglycol-derived diamino linker featuring (+)-ionizable sites was employed to link the two functional moieties, affording two unprecedented Ru conjugates with 1:1 and 2:1 stoichiometry of aminoquinazoline to the Ru complex (mono-quinazoline-Ru-conjugate and bis-quinazoline-Ru-conjugate, respectively). The bis-quinazoline-Ru-conjugate, which retains an essential inhibitory activity, was found by fluorescence imaging to be effectively uptaken by Uppsala 87 malignant glioma (grade IV malignant glioma) cells. The fluorescence imaging study and a time-resolved fluorescence resonance energy transfer study indicated a specific subcellular distribution of the conjugate that coincides with that of a mitochondria-targeted dye, suggesting mitochondrial localization of the conjugate and potential association with mitochondria-translocated forms of EGFR. Mitochondrial localization was further documented by the specific concentration of the bis-quinazoline-Ru-conjugate in a mitochondrial isolation assay.
- Ilmi, Rashid,Tseriotou, Eleni,Stylianou, Panayiota,Christou, Yiota A.,Ttofi, Iakovia,Dietis, Nikolas,Pitris, Costas,Odysseos, Andreani D.,Georgiades, Savvas N.
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p. 4260 - 4273
(2019/10/16)
-
- Quinazoline-Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
-
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
-
-
- Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7
-
Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5–10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies. Due to a lack of high-resolution DUB?small-molecule ligand complex structures, no structure-guided optimization efforts have been reported for a mammalian DUB. Here, we report a small-molecule?ubiquitin-specific protease (USP) family DUB co-structure and rapid design of potent and selective inhibitors of USP7 guided by the structure. Interestingly, the compounds are non-covalent active-site inhibitors. Lamberto et al. report the structure-guided development of inhibitors of the deubiquitinating enzyme (DUB) USP7. The studies provide optimized and well-characterized probes for studying USP7 in normal and disease biology and, furthermore, lend validation to the notion that potent and selective active-site inhibitors of DUBs can be achieved.
- Lamberto, Ilaria,Liu, Xiaoxi,Seo, Hyuk-Soo,Schauer, Nathan J.,Iacob, Roxana E.,Hu, Wanyi,Das, Deepika,Mikhailova, Tatiana,Weisberg, Ellen L.,Engen, John R.,Anderson, Kenneth C.,Chauhan, Dharminder,Dhe-Paganon, Sirano,Buhrlage, Sara J.
-
p. 1490 - 11,1500
(2017/10/26)
-
- COMPOUNDS AND METHODS FOR INHIBITING VACUOLAR ATPASE
-
A compound of Formula II, is provided. R1, R2 and R3 are independently either hydrogen, alkyl, aryl, halogen, alkoxy, nitro, amino or hydroxyl. X is either F, Cl, Br, I or CN. Y is either N or CH. Compositions that include Formula II can be used to inhibit vacuolar H+ ATPase.
- -
-
Paragraph 0045
(2017/07/14)
-
- Design, Synthesis, and Potency of Pyruvate Dehydrogenase Complex E1 Inhibitors against Cyanobacteria
-
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)
-
- A microwave catalysis in the aqueous phase a method of preparing Quinazolinone compounds
-
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.
- -
-
Paragraph 0058
(2017/02/09)
-
- Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3
-
Erythropoietin-producing human hepatocellular carcinoma (Eph) receptor tyrosine kinases (RTKs) regulate a variety of dynamic cellular events, including cell protrusion, migration, proliferation, and cell-fate determination. Small-molecule inhibitors of Eph kinases are valuable tools for dissecting the physiological and pathological roles of Eph. However, there is a lack of small-molecule inhibitors that are selective for individual Eph isoforms due to the high homology within the family. Herein, we report the development of the first potent and specific inhibitors of a single Eph isoform, EphB3. Through structural bioinformatic analysis, we identified a cysteine in the hinge region of the EphB3 kinase domain, a feature that is not shared with any other human kinases. We synthesized and characterized a series of electrophilic quinazolines to target this unique, reactive feature in EphB3. Some of the electrophilic quinazolines selectively and potently inhibited EphB3 both in vitro and in cells. Cocrystal structures of EphB3 in complex with two quinazolines confirmed the covalent linkage between the protein and the inhibitors. A "clickable" version of an optimized inhibitor was created and employed to verify specific target engagement in the whole proteome and to probe the extent and kinetics of target engagement of existing EphB3 inhibitors. Furthermore, we demonstrate that the autophosphorylation of EphB3 within the juxtamembrane region occurs in trans using a specific inhibitor. These exquisitely specific inhibitors will facilitate the dissection of EphB3's role in various biological processes and disease contribution.
- Kung, Alvin,Chen, Ying-Chu,Schimpl, Marianne,Ni, Feng,Zhu, Jianfa,Turner, Maurice,Molina, Henrik,Overman, Ross,Zhang, Chao
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supporting information
p. 10554 - 10560
(2016/09/04)
-
- Phenyl [...] compound and its preparation method, pharmaceutical composition, drug use (by machine translation)
-
The invention provides a phenylurea coupling quinazoline compound or a pharmaceutically acceptable salt thereof represented by formula (I), wherein R1 represents H, represents Br, Cl or F, represents -CH3, -CH2-CH3, -CH2(CH3)2 or -CF3, represents -O-CH3, -O-CH2-CH3 or -O-CH2(CH3)2, or represents -C[triple bond]CH or -C[triple bond]N; n1 is 1, 2, 3, 4 or 5; one of R2 and R3 is a group represented by formula (II); R4 represents H, represents Br, Cl or F, represents -CH3, -CH2-CH3, -CH2(CH3)2 or -CF3, represents -O-CH3, -O-CH2-CH3 or -O-CH2(CH3)2, represents -NH2, or represents -NO2; n2 is 1, 2, 3, 4 or 5; and the other one of R2 and R3 represents H, -O-CH3, -O-CH2-CH3, -O-CH2(CH3)2, or the following groups.
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-
Paragraph 0113; 0115-0117
(2016/10/27)
-
- Antiviral agents
-
This invention relates to compounds of formula I their salts, and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions comprising these compounds and their use in the treatment of picornavirus infections in mammals, as well as nove
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Page/Page column 26
(2016/05/02)
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- PROTOTYPE SYSTEMS OF THERANOSTIC BIOMARKERS FOR IN VIVO MOLECULAR MANAGEMENT OF CANCER
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The present invention relates to a theranostic system comprising a beacon and a compound selected from the group consisting of a quinazoline-based tyrosine kinase inhibitor and a natural product. The theranostic systems have use in the therapy and diagnosis of tyrosine kinase related malignancies.
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-
Paragraph 0220
(2017/01/19)
-
- Quinazoline derivatives and their use
-
The present invention provides a quinazoline compound shown in formula (I), or pharmaceutically acceptable salt thereof. R1, R2 and R7 are independently and respectively selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, halogenate C1-6 alkyl, halogenate C1
- -
-
Paragraph 0228; 0244; 0245
(2016/10/08)
-
- FACTOR IXA INHIBITORS
-
The present invention provides a compound of Formula (I) (structurally represented) wherein R1 is H or C1-6 alkyl, R2 is H or C1-6 alkyl or CH20H, R3 is H or C1-6 alkyl, and R4 is H or C1-6 alkyl, provided that when R1, R2, and R3 are H, R4 is C1-6 alkyl, and when R1, R2, and R4 are H, then R3 is C1-6 alkyl, and when R1, R3, and R4 are H, R2 is C1-6 alkyl or-CH20H, and when R2, R3, and R4 are H, then R1 is C 1-6 alkyl; A is 1 ) a 9-10 membered bicyclic heterocycle having 1-3 heteroatoms independently selected from N, S and 0, which 9-10 membered bicyclic heterocycle is unsubstituted or substituted with R5 and unsubstituted or substituted with R6 and unsubstituted or substituted with NH2, or 2) a 6-9 membered monocyclic or bicyclic carbocyclic ring system unsubstituted or substituted with R5, unsubstituted or substituted with R6, and unsubstituted or substituted with -CH2NH2; and B is 1) a 5- or 6-membered monocyclic heterocycle having 1 or 2 heteroatoms independently selected from N, S or 0, which is unsubstituted or substituted on a carbon or nitrogen atom with R7, unsubstituted or substituted on a carbon or nitrogen atom with R8, and unsubstituted or substituted on a carbon or nitrogen atom with R9, or 2) an 8- or 9-membered fused bicyclic heterocycle having 1, 2 or 3 nitrogen atoms which is unsubstituted or substituted on a carbon or nitrogen atom with R7, and unsubstituted or substituted on a carbon or nitrogen atom with R8; and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses.
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Page/Page column 33
(2014/08/19)
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- Synthesis and SAR optimization of quinazolin-4(3H)-ones as poly(ADP-ribose)polymerase-1 inhibitors
-
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)
-
- Vibrational spectroscopic investigation and theoretical calculations of (E)-3-phenyl-N-[4-(Phenyl-Amino) quinazoline-7-yl] acrylamide
-
Optimized geometrical structure and harmonic vibration frequencies of prior synthesized (E)-3-phenyl-N-[4-(phenyl-amino) quinazoline-7-yl] acrylamide were computed by ab initio HF and DFT/B3LYP methods using both 6-31G* and 6-311G* basis sets and the Moll
- Zheng, Qing,Dai, Yong,Han, Xiangyun,Zhang, Yang
-
supporting information
p. 530 - 540,11
(2020/09/16)
-
- Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account
-
Two closely related scaffolds were identified through an uHTS campaign as desirable starting points for the development of Rho-Kinase (ROCK) inhibitors. Here, we describe our hit-to-lead evaluation process which culminated in the rapid discovery of potent leads such as 22 which successfully demonstrated an early in vivo proof of concept for anti-hypertensive activity.
- Wu, Frank,Büttner, Frank H.,Chen, Rhonda,Hickey, Eugene,Jakes, Scott,Kaplita, Paul,Kashem, Mohammed A.,Kerr, Steven,Kugler, Stanley,Paw, Zofia,Prokopowicz, Anthony,Shih, Cheng-Kon,Snow, Roger,Young, Erick,Cywin, Charles L.
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scheme or table
p. 3235 - 3239
(2010/08/22)
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- QUINAZOLINE DERIVATIVES
-
Quinazoline derivatives of the following formula: wherein R1, R2, R3, R4, R5, X, Y, and Z are defined herein. It also discloses a method of treating cancer with one of these compounds.
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Page/Page column 26-27
(2010/02/17)
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- RHO KINASE INHIBITORS
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Disclosed are novel substituted 2H-isoquinolin-1-one and 3H-quinazolin-4-one derivatives useful as inhibitors of Rho kinase and for treating a variety of diseases and disorders that are mediated or sustained through the activity of Rho kinase, including c
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Page/Page column 46
(2008/12/06)
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- Antiviral agents
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This invention relates to compounds of formula I their salts, and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions comprising these compounds and their use in the treatment of picornavirus infections in mammals as well as novel
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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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- Efficient synthesis of thiazoloquinazolinone derivatives
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An original route to the rare 8H-thiazolo[5,4-f]quinazolin-9-one 1 and the novel 7H-thiazolo[4,5-h]quinazolin-6-one 2 is described. Access to the regioisomers was realized by fusion of a thiazole and a quinazoline ring via Appel's salt chemistry. Thermal
- Alexandre, Fran?ois-René,Berecibar, Amaya,Wrigglesworth, Roger,Besson, Thierry
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p. 4455 - 4458
(2007/10/03)
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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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- 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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- 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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