- Ru-NHC-Catalyzed Asymmetric Hydrogenation of 2-Quinolones to Chiral 3,4-Dihydro-2-Quinolones
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Direct enantioselective hydrogenation of unsaturated compounds to generate chiral three-dimensional motifs is one of the most straightforward and important approaches in synthetic chemistry. We realized the Ru(II)-NHC-catalyzed asymmetric hydrogenation of 2-quinolones under mild reaction conditions. Alkyl-, aryl- and halogen-substituted optically active dihydro-2-quinolones were obtained in high yields with moderate to excellent enantioselectivities. The reaction provides an efficient and atom-economic pathway to construct simple chiral 3,4-dihydro-2-quinolones. The desired products could be further reduced to tetrahydroquinolines and octahydroquinolones.
- Daniliuc, Constantin,Glorius, Frank,Hu, Tianjiao,Lückemeier, Lukas
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supporting information
p. 23193 - 23196
(2021/09/25)
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- HFIP-mediated strategy towards β-oxo amides and subsequent Friedel-Craft type cyclization to 2?quinolinones using recyclable catalyst
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A simple and cost-effective 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)-mediated protocol for the synthesis of β-oxo amides has been described by using amines and β-keto esters as substrates. The reaction conditions were found to be highly efficient towards the cleavage of C[sbnd]O bond and consequent formation of the products in excellent yields and selectivity. The obtained β-oxo amides were further transformed in to the synthetically useful 2?quinolinones via intramolecular Friedel-Craft type cyclization of aromatic ring using ferrites as a recyclable catalyst. A spectrum of substrates bearing broad range of functional groups were well tolerated under the reaction conditions. The proposed mechanistic pathways were substantially verified by literature and mass-spectroscopic evidences.
- Kabi, Arup K.,Gujjarappa, Raghuram,Vodnala, Nagaraju,Kaldhi, Dhananjaya,Tyagi, Ujjawal,Mukherjee, Kalisadhan,Malakar, Chandi C.
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supporting information
(2020/10/20)
-
- Virtual screening and optimization of novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma
-
Background: Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC. Methods: A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K. The radiosensitizing effect of the optimized compound (2a) was confirmed by colony formation assays and DNA double-strand break assays in vitro. The discovery and preclinical characteristics of this compound are described. Results: The key amino acid residues in mTOR were identified, and a precise virtual screening model was constructed. Compound 2a, with a 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine scaffold, exhibited promising potency against mTOR (mTOR IC50=7.1 nmol/L (nM)) with 126-fold selectivity over PI3Kα.Moreover, 2a significantly enhanced the sensitivity of HCC to radiotherapy in vitro in a dose-dependent manner. Conclusion: A new class of selective mTOR inhibitors was developed and their radiosensitization effects were confirmed. This study also provides a basis for developing mTORspecific inhibitors for use as radiosensitizers for HCC radiotherapy.
- Cao, Shuang,Chen, Jian-Chao,Chen, Yong-Shou,Feng, Ying-Qi,Gao, Xu-Dong,Gu, Shuang-Xi,Lu, Yin-Ying,Ren, Yi-Xin,Zhang, Heng
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p. 1779 - 1798
(2020/06/21)
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- 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors
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Chronic hepatitis B virus (HBV) infection represents a major health threat. Current FDA-approved drugs do not cure HBV. Targeting HBV core protein (Cp) provides an attractive approach toward HBV inhibition and possibly infection cure. We have previously identified and characterized a 5-amino-3-methylthiophene-2,4-dicarboxamide (ATDC) compound as a structurally novel hit for capsid assembly effectors (CAEs). We report herein hit validation through studies on absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK), and hit optimization via analogue synthesis aiming to probe the structure-activity relationship (SAR) and structure-property relationship (SPR). In the end, these medicinal chemistry efforts led to the identification of multiple analogues strongly binding to Cp, potently inhibiting HBV replication in nanomolar range without cytotoxicity, and exhibiting good oral bioavailability (F). Two of our analogues, 19o (EC50 = 0.11 μM, CC50 > 100 μM, F = 25%) and 19k (EC50 = 0.31 μM, CC50 > 100 μM, F = 46%), displayed overall lead profiles superior to reported CAEs 7–10 used in our studies.
- Tang, Jing,Huber, Andrew D.,Pineda, Dallas L.,Boschert, Kelsey N.,Wolf, Jennifer J.,Kankanala, Jayakanth,Xie, Jiashu,Sarafianos, Stefan G.,Wang, Zhengqiang
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supporting information
p. 179 - 192
(2019/01/04)
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- Gold-Catalyzed Dearomative Spirocyclization of N-Aryl Alkynamides for the Synthesis of Spirolactams
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A catalytic redox-neutral method for the synthesis of spirolactams proceeding through the dearomative spirocyclization of N-aryl alkynamides is reported. In contrast to stoichiometric activating agents employed for related transformations, we show that the use of 5 mol % of Au(PPh3)Cl and AgOTf in dichloroethane at 50-80 °C leads to selective spirocyclization, furnishing the products in yields of 35-87%. The substrate scope of the reaction is good, with both electron-donating and electron-withdrawing groups being tolerated around the arene ring, as well as substitution at the amide nitrogen. The identity of the para-alkoxy group on the arene ring is key to achieving selectivity for spirocyclization over alternative mechanistic pathways. While the presence of a para-methoxy group leads to trace amounts of the desired spirolactams, the para-tert-butoxy or para-hydroxy substrate analogues furnish the spirolactams in good yield with high selectivity.
- Vacala, Taylor L.,Carlson, Paul R.,Arreola-Hester, Asa,Williams, Chloé G.,Makhoul, Evana W.,Vadola, Paul A.
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p. 1493 - 1501
(2018/02/10)
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- Compounds having anticonvulsion activity, preparing methods thereof and applications of the compounds
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The invention provides 7-substituted-5-methyl-1,2,4-triazolo[4,3-a] quinoline and 7-substituted-5-ethoxy-[1,2,4]-triazolo[4,3-a] quinoline compounds having anticonvulsion activity, preparing methods thereof and applications of the compounds in the field of preparing anticonvulsion medicines.
- -
-
Paragraph 0041; 0042; 0043; 0044
(2017/10/05)
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- Novel 5-oxo-hexahydroquinoline derivatives: Design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study
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Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C4 and various carboxamide substituents at C3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells’ sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C4 position and compounds with 4-chlorophenyl carboxamide at C3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 μM, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 μM, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal.
- Shahraki, Omolbanin,Edraki, Najmeh,Khoshneviszadeh, Mehdi,Zargari, Farshid,Ranjbar, Sara,Saso, Luciano,Firuzi, Omidreza,Miri, Ramin
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p. 407 - 418
(2017/02/26)
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- Effective microwave synthesis of bioactive thieno[2,3-d]pyrimidines
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A series of novel 2-Amino-3-cyanothiophenes (2a-2j) were synthesized using heterogeneous base (K2CO3) supported Gewald reaction. Cyclization of 2a-j with formamide and urea in conventional heating as well as microwave irradiation gave thieno[2,3-d]pyrimidines (3a-3j) and thieno[2,3-d]pyrimidin-2(1H)-ones(4a-4j) respectively. The reaction rates were faster and yields were higher in the microwave conditions. The structures of the compounds were confirmed with elemental analysis, mass spectral analysis, FTIR, 1H NMR and 13C NMR techniques. All the synthesized compounds were subjected to antimicrobial activity (MIC) in vitro by broth dilution method and exhibited a moderate antimicrobial activity.
- Khatri, Taslimahemad T.,Shah, Viresh H.
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p. 3354 - 3358
(2017/05/22)
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- Design and synthesis of novel coumarin analogs and their nematicidal activity against five phytonematodes
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The presence of hydroxyl groups at the C4 and C7 positions in coumarin backbone has been proposed as a potential modification site for providing excellent bioactivity according to previous studies. A series of novel coumarin derivatives were rationally designed and synthesized by use of a complex catalytic system for a targeted modification at the above sites. These derivatives were assayed for nematicidal activity. As predicted, the derivatization enhanced the activity of the coumarins against five nematodes. Compounds 7b, 9a, 10c and 11c showed significant strong nematicidal broad spectrum activity against all tested nematodes. Compound 10c was the most effective with the lowest LC50 values against Meloidogyne incognita (5.1 μmol/L), Ditylenchus destructor (3.7 μmol/L), Bursaphelenchus mucronatus (6.4 μmol/L), Bursaphelenchus B. xylophilus (2.5 μmol/L) and Aphelenchoides besseyi (3.1 μmol/L), respectively. A brief investigation on the structure-activity relationships (SAR) revealed that the targeted modification by a C7 hydroxyl was optimum compared with that of a C4 hydroxyl and that the coupling chain length was crucial for the nematicidal activity.
- Pan, Le,Li, Xiu-Zhuang,Sun, Di-An,Jin, Hui,Guo, Hong-Ru,Qin, Bo
-
supporting information
p. 375 - 379
(2016/03/19)
-
- Design, Multicomponent Synthesis and Characterization of Diversely Substituted Pyrazolo[1,5-a] Pyrimidine Derivatives
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The synthesis of various heterocyclic compounds using acetoacetanilide[AAA], we have demonstrated that acetoactanilide are versatile intermediate for the synthesis of pyrazolopyrimidine derivatives. Thus, to explore further, we sought that the reaction of various acetoactanilide, an appropriate aldehyde and 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-carboxamide in the presence of base in isopropyl alcohol could be an effective strategy to furnish the novel pyrazolopyrimidine derivatives. Here we describe the novel synthetic methodology for the fused pyrazolopyrimidines.
- Ghelani, Satish M.,Naliapara, Yogesh T.
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p. 1843 - 1851
(2016/11/23)
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- An efficient green protocol for the preparation of acetoacetamides and application of the methodology to a one-pot synthesis of Biginelli dihydropyrimidines. Expansion of dihydropyrimidine topological chemical space
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The present study describes the preparation of N-aryl-(15) and N-alkyl-(17) acetoacetamides, in good to excellent yields, using both conventional and microwave heating, by reaction of amine derivatives (14 and 16) with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (TMD, 12) in aqueous medium. The acetoacetamides were used to prepare novel Biginelli dihydropyrimidine derivatives. The introduction of the amino acid derivatives potentially allows for the exploration of new structural complexity and topologically diversifies the chemical space occupied by this versatile chemical scaffold.
- Gama, Fernando H. S.,De Souza, Rodrigo O. M. A.,Garden, Simon J.
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p. 70915 - 70928
(2015/09/08)
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- Silver(I)-catalyzed tandem approach to β-oxo amides
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A facile and efficient AgI-catalytic approach is reported for the first time to synthesize β-oxo amides from β-oxo esters a with broad substrate scope in good to excellent yields. Crossover and in situ NMR studies confirmed that the reaction occurred through a new pathway and not by the traditional condensation reaction. The key advantages of this method are the readily available starting materials, the air-stable reaction, the simple protocol, and the environmental friendliness. A new, catalytic approach to the synthesis of β-oxo amides from β-oxo esters with a broad substrate scope in good to excellent yields was developed. In situ NMR spectroscopy and crossover experiments confirmed the reaction mechanism.
- Vandavasi, Jaya Kishore,Hsiao, Cheng-Tien,Hu, Wan-Ping,Boominathan, Siva Senthil Kumar,Wang, Jeh-Jeng
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supporting information
p. 3171 - 3177
(2015/05/13)
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- Multicomponent strategy to indeno[2,1- C ]pyridine and hydroisoquinoline derivatives through cleavage of carbon-carbon bond
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A concise and efficient three-component domino reaction has been developed for the synthesis of polyfunctionalized indenopyridine and hydroisoquinoline derivatives via the cleavage of a C-C bond under transition-metal-free conditions. This reaction provides facile access to complex nitrogen-containing heterocycles by simply mixing three common starting materials in EtOH in the presence of 20 mol % NaOH under microwave irradiation conditions.
- Feng, Xian,Wang, Jian-Jun,Xun, Zhan,Huang, Zhi-Bin,Shi, Da-Qing
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p. 1025 - 1033
(2015/01/30)
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- Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening
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Histone methyltransferases are involved in various biological functions, and these methylation regulating enzymes' abnormal expression or activity has been noted in several human cancers. Within this context, SET domain-containing (lysine methyltransferase) 7 (SET7, also called KMT7, SETD7, SET9) is of increasing significance due to its diverse roles in biological functions and diseases, such as diabetes, cancers, alopecia areata, atherosclerotic vascular disease, HIV, and HCV. In this study, DC-S100, which was discovered by pharmacophore- and docking-based virtual screening, was identified as the hit compound of SET7 inhibitor. Structure-activity relationship (SAR) analysis was performed on analogs of DC-S100 and according to the putative binding mode of DC-S100, structure modifications were made to improve its activity. Of note, compounds DC-S238 and DC-S239, with IC50 values of 4.88 and 4.59 μM, respectively, displayed selectivity for DNMT1, DOT1L, EZH2, NSD1, SETD8, and G9a. Taken together, DC-S238 and DC-S239 can serve as leads for further investigation as SET7 inhibitors and the chemical toolkits for functional biology studies of SET7.
- Meng, Fanwang,Cheng, Sufang,Ding, Hong,Liu, Shien,Liu, Yan,Zhu, Kongkai,Chen, Shijie,Lu, Junyan,Xie, Yiqian,Li, Linjuan,Liu, Rongfeng,Shi, Zhe,Zhou, Yu,Liu, Yu-Chih,Zheng, Mingyue,Jiang, Hualiang,Lu, Wencong,Liu, Hong,Luo, Cheng
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p. 8166 - 8181
(2015/11/09)
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- Targeting dormant tuberculosis bacilli: Results for molecules with a novel pyrimidone scaffold
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Our inability to completely control TB has been due in part to the presence of dormant mycobacteria. This also renders drug regimens ineffective and is the prime cause of the appearance of drug-resistant strains. In continuation of our efforts to develop novel antitubercular agents that especially target dormant mycobacteria, a set of 55 new compounds belonging to the pyrimidone class were designed on the basis of CoMFA and CoMSIA studies, and these were synthesized and subsequently tested against both the dormant and virulent BCG strain of M. tuberculosis. Some novel compounds have been identified which selectively inhibit the dormant tuberculosis bacilli with significantly low IC50 values. This study reports the second molecule after TMC-207, having the ability to inhibit tuberculosis bacilli exclusively in its dormant phase. The synthesis was accomplished by a modified multicomponent Biginelli reaction. A classification model was generated using the binary QSAR approach - recursive partitioning (RP) to identify structural characteristics related to the activity. Physicochemical, structural, topological, connectivity indices, and E-state key descriptors were used for generation of the decision tree. The decision tree could provide insights into structure-activity relationships that will guide the design of more potent inhibitors. This paper reports the second molecule after TMC-207, with the ability to inhibit tuberculosis bacilli in its dormant phase. The paper reports molecules with a novel Pyrimidone Scaffold, the synthesis of which was accomplished with a modified multi-component Biginelli reaction. A classification model was generated using recursive partitioning (RP) technique to identify structural characteristics of the molecules with their varying activities.
- Joshi, Rohit R.,Barchha, Avinash,Khedkar, Vijay M.,Pissurlenkar, Raghuvir R. S.,Sarkar, Sampa,Sarkar, Dhiman,Joshi, Rohini R.,Joshi, Ramesh A.,Shah, Anamik K.,Coutinho, Evans C.
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p. 201 - 207
(2015/01/30)
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- Ligand-enabled γ-C-H olefination and carbonylation: Construction of β-quaternary carbon centers
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Monoselective γ-C-H olefination and carbonylation of aliphatic acids has been accomplished by using a combination of a quinoline-based ligand and a weakly coordinating amide directing group. The reaction provides a new route for constructing richly functionalized all-carbon quaternary carbon centers at the β-position of aliphatic acids.
- Li, Suhua,Chen, Gang,Feng, Chen-Guo,Gong, Wei,Yu, Jin-Quan
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supporting information
p. 5267 - 5270
(2014/05/06)
-
- Facile eco-friendly synthesis of novel chromeno[4,3-b]pyridine-2,5-diones and evaluation of their antimicrobial and antioxidant properties
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Rapid and facileaccess to novel chromeno[4,3-b]pyridine-2,5-dione derivatives was achieved by a mild base catalysed reaction of 4-chloro-3-formylcoumarin and acetoacetamides in PEG-300 as recyclable solvent. The compounds were evaluated for their antimicrobial activities against 3 Gram-positive and 3 Gram-negative bacteria (Staphylococcus epidermis, Vibrio parahaemolyticus, Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Klebsiella pneumonia) with Cefotaxime control. They were further subjected to antioxidant studies using DPPH test with ascorbic acid control. While compounds 5d and 5k showed promising broad spectrum antibacterial properties against all the evaluated bacteria, compound 5g exhibited good antioxidant properties. Indian Academy of Sciences.
- Jaggavarapu, Satyanarayana Reddy,Kamalakaran, Anand Solomon,Jalli, Ventkata Prasad,Gangisetty, Sravan Kumar,Ganesh, Munusswamy Ramanujam,Gaddamanugu, Gopikrishna
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p. 187 - 195
(2014/04/03)
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- Facile eco-friendly synthesis of novel chromeno[4,3-b]pyridine-2,5-diones and evaluation of their antimicrobial and antioxidant properties
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Rapid and facile access to novel chromeno[4,3-b]pyridine-2,5-dione derivatives was achieved by a mild base catalysed reaction of 4-chloro-3-formylcoumarin and acetoacetamides in PEG-300 as recyclable solvent. The compounds were evaluated for their antimicrobial activities against 3 Gram-positive and 3 Gram-negative bacteria (Staphylococcus epidermis, Vibrio parahaemolyticus, Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Klebsiella pneumonia) with Cefotaxime control. They were further subjected to antioxidant studies using DPPH test with ascorbic acid control. While compounds 5d and 5k showed promising broad spectrum antibacterial properties against all the evaluated bacteria, compound 5g exhibited good antioxidant properties. [Figure not available: see fulltext.]
- Jaggavarapu, Satyanarayana Reddy,Kamalakaran, Anand Solomon,Jalli, Ventkata Prasad,Gangisetty, Sravan Kumar,Ganesh, Munusswamy Ramanujam,Gaddamanugu, Gopikrishna
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p. 187 - 195
(2016/02/26)
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- One-pot synthesis of 3-hydroxyquinolin-2(1 H)-ones from N-phenylacetoacetamide via PhI(OCOCF3)2-mediated α-hydroxylation and H2SO4-promoted intramolecular cyclization
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A clean, one-pot synthesis of the biologically important 3-hydroxyquinolin-2(1H)-one compounds has been realized from the readily available N-phenylacetoacetamide derivatives through a PhI(OCOCF 3)2-mediated α-hydroxylation and a H 2SO4-promoted intramolecular condensation. The hydroxyl group in the generated α-hydroxylated intermediate can be well tolerated in the second H2SO4-promoted cyclization step.
- Yuan, Yucheng,Yang, Rui,Zhang-Negrerie, Daisy,Wang, Junwei,Du, Yunfei,Zhao, Kang
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p. 5385 - 5392
(2013/07/26)
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- Facile synthesis of furoquinoline and effects on radical-induced oxidation of DNA
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The aim of this work was to clarify the influences of the position of hydroxyl group and furo[2,3-b] moiety on the antioxidant effectiveness of quinoline. Thus, 4-methyl-2,3-dihydrofuro[2,3-b]quinolin-6-ol (PFQ), 4-methyl-2,3-dihydrofuro[2,3-b]quinolin-8-ol (OFQ), and 4-methyl-2,3- dihydrofuro[2,3-b]quinolin-7-ol (MFQ) were synthesized by a recyclization reaction of 1-acetyl-N-phenylcyclopropanecarboxamide in the presence of SnCl4 as the catalyst. The antioxidant capacities of PFQ, OFQ, and MFQ were evaluated in the experimental system of the oxidation of DNA caused by Cu2+/glutathione (GSH), ?OH, and 2,2′-azobis(2- amidinopropane hydrochloride) (AAPH). OFQ and PFQ were able to protect DNA against Cu2+/GSH- and ?OH-induced oxidation because the furo[2,3-b] moiety was beneficial for stabilizing the produced furoquinoline radical. Moreover, MFQ can decrease the oxidation rate of AAPH-induced oxidation of DNA, while PFQ and OFQ can inhibit AAPH-induced oxidation of DNA for a period. The data obtained from AAPH-induced oxidation of DNA were treated by chemical kinetic method; it was found that PFQ and OFQ can trap 1.3 and 1.5 radicals, respectively. Therefore, the hydroxyl group at different positions changed the mechanism of furoquinoline in protecting DNA against radical-induced oxidation. Graphical Abstract: Effects on Cu2+/glutathione-, ?OH-, and peroxyl radical-induced oxidation of DNA.[Figure not available: see fulltext.]
- Wang, Rui,Liu, Zai-Qun
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p. 1563 - 1569
(2013/07/26)
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- Synthesis and in vitro anticancer and antitubercular activity of diarylpyrazole ligated dihydropyrimidines possessing lipophilic carbamoyl group
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A series of dihydropyrimidine derivatives were synthesized by utilizing Biginelli reaction and evaluated for their in vitro anticancer activity against MCF-7 human breast cancer (HBC) cell line using sulforhodamine B (SRB) assay and antitubercular activity against Mycobacterium tuberculosis (MTB) H 37Rv using Microplate Alamar Blue Assay (MABA). Compounds 13p, 13t were exhibited 70.6% and 63.7% of HBC cell growth inhibition at 10 μM concentration. Interestingly compound 13p was also found to be the most potent in the series against MTB H37Rv with MIC value of 0.125 μg/mL.
- Yadlapalli, Rama Krishna,Chourasia,Vemuri, Kiranmayi,Sritharan, Manjula,Perali, Ramu Sridhar
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supporting information; experimental part
p. 2708 - 2711
(2012/05/20)
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- Straightforward access to (imidazol-2-yl)acetates by reaction of 2-unsubstituted imidazole 3-oxides with dimethyl acetylenedicarboxylate
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A new method for the preparation of 1,4,5-trisubstituted (imidazol-2-yl)acetates, based on the reaction of the corresponding imidazole 3-oxides with dimethyl acetylenedicarboxylate (DMAD) is described. Formation of the products is rationalized by a formal 1,3-dipolar cycloaddition and subsequent oxaloyl cleavage. 1,4,5-Trisubstituted imidazole 3-oxides bearing an electron-withdrawing substituent at C(4), easily react with dimethyl acetylenedicarboxylate (DMAD), yielding the corresponding oxobutanoates, which subsequently, in a one-pot procedure undergo hydrolysis through an "oxaloyl cleavage" mode. New (imidazol-2-yl)acetates were isolated in high yields. Copyright
- Mlostoń, Grzegorz,Jasiński, Marcin,Heimgartner, Heinz
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scheme or table
p. 2542 - 2547
(2011/05/16)
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- Synthesis of novel Hantzsch dihydropyridines and Biginelli dihydropyrimidines of biological interest: A 3D-QSAR study on their cytotoxicity
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We report a library consisting of some novel Hantzsch dihydropyridines and Biginelli dihydropyrimidines of biological interest as well as their synthesis and analysis. The important steps in the synthetic part were found to be Hantzsch and Biginelli multicomponent reactions. The synthesized compounds were screened for their in vitro antibacterial activity against two gram-positive bacteria: Staphylococcus aureus and Bacillus subtilis. The title compounds did not exhibit potential antibacterial activity. Furthermore, compounds were subjected to in vitro cytotoxicity against Vero cells. Compounds exhibited weak, moderate, or high cytotoxicity. Compounds 4a, 4b, 4c, 4f, 4g, 4h, 4i, 7i, 7l, 7m, and 7r exhibited potential cytotoxicity. CoMFA study has resulted in the identification of structural features contributing toward their cytotoxicity.
- Prashantha Kumar,Masih, Pankaj,Karthikeyan,Bansal, Ankur,Suja,Vijayan, Pottekad
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experimental part
p. 344 - 363
(2011/02/25)
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- Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents
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Four series of dihydropyrazolo[3,4-b]pyridines and benzo[4,5]imidazo[1,2-a] pyrimidines were designed and synthesized as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents by introducing some fragments of Aurora-A kinase inhibitors into our KSP inhibitor CPUYL064. A total of 19 target compounds were evaluated by two related enzyme inhibition assays and a cytotoxicity assay in vitro. The results showed that some target compounds could inhibit both enzymes, and several of them showed significant inhibition activity against HCT116 cell line. Despite showing moderate KSP and Aurora-A kinase inhibition, the lead compounds 6a and 6e displayed significant cytotoxic activity in the micromolar range, especially against the HCT116 cell line and HepG2 cell line. The results may be useful for developing a new class of inhibitors having a dual function, KSP inhibition and Aurora-A kinase inhibition, for the treatment of cancer.
- Fu, Rong-Geng,You, Qi-Dong,Yang, Lei,Wu, Wu-Tong,Jiang, Cheng,Xu, Xiao-Li
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experimental part
p. 8035 - 8043
(2011/02/22)
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- Characterization of 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl acetate as an effective antiplatelet agent
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We have studied earlier a membrane bound novel enzyme Acetoxy Drug: protein transacetylase identified as Calreticulin Transacetylase (CRTAase) that catalyzes the transfer of acetyl groups from polyphenolic acetates (PAs) to the receptor proteins and thus modulating their biological activities. In this communication, we have reported for the first time that acetoxy quinolones are endowed with antiplatelet action by virtue of causing CRTAase catalyzed activation of platelet Nitric Oxide Synthase (NOS) by way of acetylation leading to the inhibition of ADP/Arachidonic acid (AA)-dependent platelet aggregation. The correlation of specificity of platelet CRTAase to various analogues of acetoxy quinolones with intracellular NO and consequent effect on inhibition of platelet aggregation was considered crucial. Among acetoxy quinolones screened, 6-AQ (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl acetate/6-acetoxyquinolin-2-one, 22) was found to be the superior substrate to platelet CRTAase and emerged as the most active entity to produce antiplatelet action both in vitro and in vivo. 6-AQ caused the inhibition of cyclooxygenase-1 (Cox-1) resulting in the down regulation of thromboxane A2 (TxA2) and the inhibition of platelet aggregation. Structural modification of acetoxy quinolones positively correlated with enhancement of intracellular NO and antiplatelet action.
- Priya, Nivedita,Gupta, Anjali,Chand, Karam,Singh, Prabhjot,Kathuria, Abha,Raj, Hanumantharao G.,Parmar, Virinder S.,Sharma, Sunil K.
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experimental part
p. 4085 - 4094
(2010/08/06)
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- Synthesis of polysubstituted 3-iodopyrans by electrophilic cyclization
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A variety of polysubstituted 3-iodopyrans were readily prepared in good to excellent yield under mild reaction conditions by the reaction of alkynyl carboxamides with ICl, I2, and NIS. The products obtained from this process are versatile mater
- Xie, Yong-Xin,Ya, Ze-Yi,Wang, Dan-Zhu,Wu, Lu-Yong,Qian, Bo,Liu, Xue-Yuan,Liang, Yong-Min
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scheme or table
p. 2283 - 2288
(2009/08/09)
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- Inter-and intra-molecular cyclisation reactions of azoacetates derived from aryl hydrazones of ethyl acetoacetate and acetoacetanilides
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The base induced cyclisations of azoacetates to azetidinones were investigated. In addition to the isolation of the desired products, it was found that 2-iminopyrrolidine-5-one derivatives as well as N-acyl hydrazides could be isolated when metal cyanides were employed as base. These entities were further modified to form pyrrolidine-2,5-diones and diazetidinones respectively. The Japan Institute of Heterocyclic Chemistry.
- O'Halloran, Neil,James, John P.,Downey, Carol A.,O'Malley, Patrick,Duff, Thomas,Bertrand, Samuel
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experimental part
p. 2681 - 2701
(2011/04/16)
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- Synthesis, screening for antitubercular activity and 3D-QSAR studies of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxamides
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Multi-drug resistance to commonly used antitubercular drugs has propelled the development of new structural classes of antitubercular agents. This paper reports the synthesis, evaluation and 3D-QSAR analysis of a set of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamides as antitubercular agents. Substituted acetoacetanilides were reacted with various aromatic aldehydes and urea which yielded the tetrahydropyrimidine derivatives with a phenyl carbamoyl group at C5 position, and with various substitutions on the 4-phenyl and the N-phenyl aromatic rings. All compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain. The QSAR models were generated on a training set of 23 molecules. The molecules were aligned using the atom-fit and field-fit techniques. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r2) of 0.98 and 0.95 with cross-validated r2(q2) of 0.68 and 0.58, respectively. The 3D-QSAR models were externally validated against a test set of 7 molecules for which the predictive r2 (rpred2) is recorded as 0.41 and 0.32 for the CoMFA and CoMSIA models, respectively. The CoMFA and CoMSIA contours helped to design some new molecules with improved activity.
- Virsodia, Vijay,Pissurlenkar, Raghuvir R.S.,Manvar, Dinesh,Dholakia, Chintan,Adlakha, Priti,Shah, Anamik,Coutinho, Evans C.
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p. 2103 - 2115
(2008/12/23)
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- Kinetics and mechanism of gas-phase pyrolysis of N-aryl-3-oxobutanamide ketoanilides, their 2-arylhydrazono derivatives, and related compounds
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Rates and products of reaction and Arrhenius activation parameters were determined for the gas-phase thermolysis of 14 substrates of the title compounds using sealed pyrex reactor tubes and HPLC/UV-VIS to monitor substrate pyrolysis. The 14 compounds under study are N-phenyl-3-oxo- (1), N-(p-chlorophenyl)-3-oxo- (2). N-(p-methylphenyl)-3-oxo- (3). and N-(p-methoxyphenyl)-3-oxobutanamide (4). in addition to (i) four substrates (5-8) obtained by the replacement of the pairs of methylene hydrogens at the 2-position of compounds (1-4), each pair by a phenylhydrazono group; (ii) three arylhydrazono derivatives (9-11) in which Cl, CH3, or OCH3 groups are substituted at the para position of the phenylhydrazono moiety of compound 5, (iii) 3-oxobutanamide (acetoacetamide. 12), N-phenyl-3-oxo-3- phenylpropanamide (13), and N,N′-diphenylpropanediamide (14). The reactions were conducted over 374-546 K temperature range, and the values of the Arrhenius log A(s-1) and Ea(kJ mol-1) of these reactions were, respectively, 120±2.0 and 119.2 ± 17.0 for the ketoanilides (1-4, 12-14), and 13.0 ± 0.7 and 157.5 ± 8.6 for the arylhyrazono compounds (5-11). Kinetically. the arylhydrazono derivatives were found to be ca. 1.4 × 103 to 5.7 × 103 times less reactive than the parent ketoanilides. A mechanism is proposed to account for reaction products and to rationalize molecular reactivities.
- Malhas, Rana N.,Al-Awadi, Nouria A.,El-Dusouqui, Osman M.E.
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- Synthesis and evaluation of some 1, 4-dihydropyridine and their derivatives as antihypertensive agents
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A series of 1, 4-dihydro-2, 6-dimethyI-4-{4-[3-(2-aminopyrazine/l-amino-4- methyl piperazine)-2-hydroxy propoxy]phenyl}-pyridine-3, 5-carbamoyl have been synthesized and the structure of the compounds have been confirmed by IR, 1H NMR, MS & elemental analysis. The title compounds have been evaluated for antihypertensive activity by tail-cuff method. Some of these compounds have been found to exhibit excellent antihypertensive activity.
- Pattan, Shashikant R.,Rasai,Venkatramana,Khade,Butle,Jadhav,Desai,Manvi
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p. 698 - 701
(2008/09/18)
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- Quinoline-4-acetamides as sPLA2 inhibitors
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Quinoline-4-acetamides were designed as potential phospholipase A2 inhibitors by structural based method and synthesized. The chemical structures of the obtained compounds were confirmed by elemental analyses, 1H NMR and MS. Preliminary bioassay study shows that quinoline-4-acetamides display certain inhibition to sPLA2.
- Liu, Ying,Feng, Yabing,Wang, Renxiao,Gao, Ying,Lai, Luhua
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p. 1639 - 1641
(2007/10/03)
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- Microwave induced acetoacetylation of hetaryl and aryl amines
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Acetoacetylation of hetaryl and aryl amines by interaction with ethyl acetoacetate under microwave irradiation, without any catalyst and/or solvent, is reported.
- Suri,Satti,Suri
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p. 3709 - 3718
(2007/10/03)
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- 4-isoxazolecarboxamide derivatives
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This invention is directed to compounds of the formula (I): STR1 wherein R1 is --OR4 (where R4 is hydrogen, lower alkyl, lower hydroxyalkyl, phenyl, phenyl-lower-alkyl, or --(CH2)n Y where n is an integer from 1 to 4 and Y is morpholino, -SR5, --C(O)OR5, --C(O)N(R6)2, --N(R6)2, or --N+ (R6)3 X-, in which R5 is lower alkyl, each R6 is independently selected from hydrogen or lower alkyl, and X is halogen) or --SR7 (where R7 is lower alkyl, phenyl-lower-alkyl, or --(CH2)n W where W is --N(R6)2 or --N+ (R6)3 X-, and n, R6 and X are as previously defined); R2 is lower alkyl, phenyl or phenyl-lower-alkyl; R3 is halo, hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or --C(O)OR5 where R5 is as previously defined; and Z is a bond, 2,5-thienyl or 2,5-furanyl; or a pharmaceutically acceptable salt thereof. These compounds are useful in treating inflammation, autoimmune disease or allograft rejection in mammals.
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- MECHANISM OF ACETOACETYLATION OF SUBSTITUED ANILINES
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Kinetics have been studied of the reaction of diketene with substituted anilines, and the reaction rate has been found to depend on relative permitivity of the system.The rate and equilibrium constants have been calculated by combination of rate and equilibrium relations with the relation by Amis; the constants correlate with the Hammett substituent constants.The reaction does not proceed as a simple bimolecular process.A reaction mechanism has been suggested.
- Knizek, Jiri,Lejdar, Erhard,Vetesnik, Pavel
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p. 365 - 374
(2007/10/02)
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- Cyclocondensations of Acetoacetanilides with 1,3,5-Trinitrobenzene-Substituent Effect in the Formation of Bicyclononane Derivatives
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Kinetics of cyclicondensation reaction of acetoacetanilide and substituted acetoacetanilides with 1,3,5-trinitrobenzene in the presence of triethylamine have been studied in 75percentDMSO-water(v/v) at 30, 35 and 40 deg C.Electron donating groups accelerate the rate of the reaction.Strongly electron withdrawing groups in the para-position require the use of ?--values for a better correlation of the rate constants.The reaction constants and the resonance parameters have been calculated.Isokinetic relationship has been established.Equilibrium constants for the formationof sodium salts of bicyclononane derivatives from sodium salts of acetoacetanilides and TNB have been calculated.
- Gnanadoss, Lalitha,Radha, N.
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p. 1077 - 1081
(2007/10/02)
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