- Highly Chemoselective Deoxygenation of N-Heterocyclic N-Oxides Using Hantzsch Esters as Mild Reducing Agents
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Herein, we disclose a highly chemoselective room-temperature deoxygenation method applicable to various functionalized N-heterocyclic N-oxides via visible light-mediated metallaphotoredox catalysis using Hantzsch esters as the sole stoichiometric reductant. Despite the feasibility of catalyst-free conditions, most of these deoxygenations can be completed within a few minutes using only a tiny amount of a catalyst. This technology also allows for multigram-scale reactions even with an extremely low catalyst loading of 0.01 mol %. The scope of this scalable and operationally convenient protocol encompasses a wide range of functional groups, such as amides, carbamates, esters, ketones, nitrile groups, nitro groups, and halogens, which provide access to the corresponding deoxygenated N-heterocycles in good to excellent yields (an average of an 86.8% yield for a total of 45 examples).
- An, Ju Hyeon,Kim, Kyu Dong,Lee, Jun Hee
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supporting information
p. 2876 - 2894
(2021/02/01)
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- Computational and Synthetic approach with Biological Evaluation of Substituted Quinoline derivatives as small molecule L858R/T790M/C797S triple mutant EGFR inhibitors targeting resistance in Non-Small Cell Lung Cancer (NSCLC)
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New substituted quinoline derivatives were designed and synthesized via a five-step modified Suzuki coupling reaction. A comparative molecular docking study was carried out on two different types of EGFR enzymes which include wild-type (PDB: 4I23) and T790M mutated (PDB: 2JIV) respectively. Compounds were also validated upon T790M/C797S mutated (PDB ID: 5D41) EGFR enzyme at the allosteric binding site. All docking studies confirmed high potency and flexibility towards wild type as well as a mutated enzyme. Anticancer activity of the synthesized derivatives was examined against HCC827, H1975 (L858R/T790M/C797S and L858R/T790M), A549, and HT-29 cell lines by standard MTT assay. Most of the quinoline derivatives revealed a significant cytotoxic effect. The IC50 values of 4-(4-methylquinolin-2-yl)phenyl 4-(chloromethyl)benzoate (5j) were found to be 0.0042 μM, 0.02 μM, 1.91 μM, 3.82 μM and 3.67 μM while IC50 values of osimertinib were 0.0040 μM, 0.02 μM, ND, 0.99 μM and 1.22 μM, respectively. Compound 5j has shown excellent inhibitory activities against EGFR kinases triple mutant with IC 50 value 1.91 μM. It was observed that, compared to H1975, A549 and A431 cell lines, synthesized compounds significantly inhibited proliferation of the HCC827 cell line. These data suggested that synthesized compounds showed promising selective anticancer activity against tumor cells harboring EGFR Del E746-A750. The potency of compound 5j was compared through molecular dynamic simulations and an insilico ADMET study. QSAR models were generated and the best model was correctly compared with respect to predicted and observed activity of compounds. The built model will assist to design, refine and construct novel substituted quinoline derivatives as potent EGFR inhibitors in near future.
- Karnik, Kshipra S.,Sarkate, Aniket P.,Tiwari, Shailee V.,Azad, Rajaram,Burra, Prasad V.L.S.,Wakte, Pravin S.
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- Free energy perturbation guided Synthesis with Biological Evaluation of Substituted Quinoline derivatives as small molecule L858R/T790M/C797S mutant EGFR inhibitors targeting resistance in Non-Small Cell Lung Cancer (NSCLC)
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Two different schemes of novel substituted quinoline derivatives were designed and synthesized via simple reaction steps and conditions. A comparative molecular docking study was carried out on two different types of EGFR enzymes which include wild-type (PDB: 4I23) and T790M mutated (PDB: 2JIV) respectively. Compounds were also validated upon T790M/C797S mutated (PDB ID: 5D41) EGFR enzyme at the allosteric binding site. Free energy perturbations were carried out to determine the absolute binding free energy of a protein–ligand complex in the form of ΔGbinding, which in turn provided 4ab and 5ad as the most potential contenders through the structural enhancement in the determined initial scaffolds. Anticancer activity of the synthesized derivatives was examined against HCC827, H1975 (L858R/T790M), A549, and HT-29 cell lines by standard MTT assay. Compound 4ad (6-chloro-2-(isoindolin-2-yl)-4-methylquinoline) has shown excellent inhibitory activities against mutant EGFR kinase with IC50 value 0.91 μM. The potency of compounds 4ab, 4ad and 5ad was compared through an insilico ADMET study.
- Azad, Rajaram,Karnik, Kshipra S.,Sarkate, Aniket P.,Tiwari, Shailee V.,Wakte, Pravin S.
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- Selective Halogenation of Pyridines Using Designed Phosphine Reagents
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Halopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C-H precursors are lacking. We designed a set of heterocyclic phosphines that are installed at the 4-position of pyridines as phosphonium salts and then displaced with halide nucleophiles. A broad range of unactivated pyridines can be halogenated, and the method is viable for late-stage halogenation of complex pharmaceuticals. Computational studies indicate that C-halogen bond formation occurs via an SNAr pathway, and phosphine elimination is the rate-determining step. Steric interactions during C-P bond cleavage account for differences in reactivity between 2- and 3-substituted pyridines.
- Alegre-Requena, Juan V.,Levy, Jeffrey N.,Liu, Renrong,McNally, Andrew,Paton, Robert S.
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supporting information
p. 11295 - 11305
(2020/07/13)
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- Synthesis and anticancer activity evaluation of some new derivatives of 2-(4-benzoyl-1-piperazinyl)-quinoline and 2-(4-cinnamoyl-1-piperazinyl)-quinoline
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In this study, we designed and synthesized twenty new derivatives of 2-(4-benzoyl-1-piperazinyl)- quinoline and 2-(4-cinnamoyl-1-piperazinyl)-quinoline with potential anticancer activity. The structures of synthesized compounds were confirmed by 1H and 13C NMR spectroscopy and MS spectrometry. The activity of novel compounds was evaluated in the cell viability assay as well as in the wound healing assay. Presented data show that examined substances have anticancer activity in cell culture. Seven compounds which showed a high rate of cell growth inhibition were selected for further studies. Three of them strongly reduced the growth of B16F10 cells. The novel compounds constitute a good base for further studies and optimization of structure for new therapeutically effective anti-cancerous drugs.
- Kubica, Krzysztof P.,Taciak, Przemys?aw P.,Czajkowska, Agnieszka,Stokfisz-Ignasiak, Alicja,Wyrebiak, Rafa?,Podsadni, Piotr,M?ynarczuk-Bia?y, Izabela,Malejczyk, Jacek,Mazurek, Aleksander P.
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p. 891 - 901
(2018/09/25)
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- Novel iron phenanthroline-based photosensitizers for antimicrobial PDT: synthesis, DNA binding and photo-induced DNA cleavage activity
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The chemistry of Fe(II) complexes showing efficient light-induced DNA cleavage activity, binding propensity to calf thymus DNA and antibacterial photodynamic therapy has been summarized in this article. Complexes of formulation [Fe(mqt)(B)2](PF6)(1)–(3), where mqt is 2-thiol-4-methylquinoline and B is N,N-donor heterocyclic base, viz. 1,10-phenanthroline, dipyrido[3,2-d:2′,3′-f]quinoxaline and dipyrido[3,2-a:2′,3′-c]phenazine have been prepared and characterized. The DNA-binding behaviors of these three complexes were explored by absorption spectra, viscosity measurements and thermal denaturation studies. The DNA binding constants for complexes (1), (2) and (3) were determined to be 1.9 × 103, 3.4 × 104 and 8.1 × 104 M?1, respectively. The experimental results suggest these complexes interact with DNA through groove-binding mode. The complexes show significant photocleavage of supercoiled DNA proceeds via a type-II process forming singlet oxygen as the reactive species. Antimicrobial photodynamic therapy was studied using photodynamic antimicrobial chemotherapy assay against Escherichia coli and all complexes exhibited significant reduction in bacterial growth on photoirradiation.
- Sudhamani, Chittanahalli N.,Bhojya Naik, Halehatty S.,Gowda, Kalligundi R. Sangeetha,Giridhar, Manju,Girija, Dugganna,Kumar, Pasupanetti N. Prashanth
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p. 1160 - 1169
(2017/05/04)
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- A practical and mild chlorination of fused heterocyclic N-oxides
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Fused azine N-oxides were selectively chlorinated at C2 in moderate to excellent yields, employing Vilsmeier reagent as both the activating agent and the nucleophilic chloride source. Remarkable features of the method include simple operation, mild reaction conditions, a wide substrate scope, and the use of only stoichiometric amount of POCl3. The potential extension of this method to a one-pot oxidation/chlorination sequence that obviates the need for isolation of the N-oxide intermediates is also validated.
- Wang, Dong,Jia, Hailing,Wang, Wuchang,Wang, Zhe
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supporting information
p. 7130 - 7132
(2015/02/02)
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- Phosphonium chloride as a non-volatile chlorinating reagent: Preparation and reaction in no solvent or ionic liquid
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Reaction of triphenylphosphine with trichloroisocyanuric acid in no solvent or an ionic liquid gave the corresponding phosphonium chloride, which can be used as a cheap and safe chlorinating reagent. Conversion of hydroxyheterocycles to chloroheterocycles, carboxylic acids to carboxylic acid chlorides, and primary amides to nitriles were accomplished by using the phosphonium chloride in excellent to good yields.
- Sugimoto, Osamu,Harada, Yukihiro,Tanji, Ken-Ichi
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p. 1583 - 1590
(2013/08/15)
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- A novel series of IKKβ inhibitors part I: Initial SAR studies of a HTS hit
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A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
- Cushing, Timothy D.,Baichwal, Vijay,Berry, Karen,Billedeau, Roland,Bordunov, Viola,Broka, Chris,Cardozo, Mario,Cheng, Peng,Clark, David,Dalrymple, Stacie,Degraffenreid, Michael,Gill, Adrian,Hao, Xiaolin,Hawley, Ronald C.,He, Xiao,Jaen, Juan C.,Labadie, Sharada S.,Labelle, Marc,Lehel, Csaba,Lu, Pu-Ping,McIntosh, Joel,Miao, Shichang,Parast, Camran,Shin, Youngsook,Sjogren, Eric B.,Smith, Marie-Louise,Talamas, Francisco X.,Tonn, George,Walker, Keith M.,Walker, Nigel P.C.,Wesche, Holger,Whitehead, Chris,Wright, Matt,Browner, Michelle F.
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scheme or table
p. 417 - 422
(2011/02/28)
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- A facile synthesis of novel 9-methyl[1,2,3]selenadiazoles[4,5-b]quinoline and 9-methyl[1,2,3]thiadiazole[4,5-b]quinoline as a new class of antimicrobial agents
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2-chloro-4-methyl quinoline 2 on condensation with semicarbazide hydrochloride gave its semicarbazone. This on reaction with SeO2 and SOCl2 yielded a new class of novel selenadiazoles 4 and thiadiazoles 5, respectively. The structure of all the compounds were elucidated on the basis of elemental analysis, IR, 1H NMR, and the mass spectral data. Some derivatives of 9-methyl[1,2,3]selenadiazole[4,5-b] quinoline and 9-methyl[1,2,3]thiadiazole [4,5-b]quinoline have been screened for antimicrobial activities. Copyright Taylor & Francis Group, LLC.
- Bhojya Naik, Halehatty S.,Ramesha, Machenahalli S.,Swetha, Boovanahalli V.,Roopa, Thopenahalli R.
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p. 533 - 541
(2007/10/03)
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- Heteroatom directed photoannulation: synthesis of indoloquinoline alkaloids: cryptolepine, cryptotackieine, cryptosanguinolentine, and their methyl derivatives
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A three-step synthesis of indoloquinoline alkaloids is described. The reaction of 2,3 and 4-substituted haloquinolines with anilines afforded the respective anilinoquinolines, which upon photocyclization gave the indoloquinolines. By regioselective methylation on quinoline nitrogen, furnished the alkaloids cryptotackieine, cryptosanguinolentine, cryptolepine, and the synthetic isomer isoneocryptolepine. Their methyl derivatives were also synthesized in search of new antiplasmodial drugs and DNA intercalating agents.
- Dhanabal,Sangeetha,Mohan
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p. 6258 - 6263
(2007/10/03)
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- Synthesis of dibenzo(b,g)-5-methyl-1,8-naphthyridines
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A series of 1,8-naphthyridines have been synthesised. 2-Hydroxy-4-methylquinoline 1 on reaction with PCI5/POCl3 gives 2-chloro-4-methylquinoline 2 which on treatment with substituted anilines yields 2-quinolinamines 3a-e. Cyclisation in situ affords the title compounds 4a-e using phosphorus oxychloride and dimethyl formamide.
- Kidwai,Kohli
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p. 248 - 249
(2007/10/03)
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- Anti-mutagenic structural modification by fluorine-substitution in highly mutagenic 4-methylquinoline derivatives
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We have previously shown that fluorine-substitution at position 3 of quinoline deprived this molecule of mutagenicity, possibly due to interference with the yield of its metabolically activated form, the 1,4-hydrated 2,3-epoxide (enamine epoxide), which is directly responsible for the mutagenic modification of DNA. To further explore the possibility of a method for anti-mutagenic modification of mutagens by fluorine-substitution, 4-methylquinoline (4-MeQ), the most mutagenic form of all the quinoline derivatives examined so far, was used as a target in the present study. Five mono- and di-fluorinated derivatives of 4-MeQ, 2-fluoro-4-methylquinoline (2-F-4-MeQ), 6-F-4-MeQ, 7-F-4-MeQ, 2,6-difluoro-4-methylquinoline (2,6-diF-4-MeQ), and 2,7-diF-4-MeQ, were subjected to analysis of their structure-mutagenicity relationships. The 2-fluorinated derivatives (2-F-4-MeQ, 2,6-diF-4-MeQ, and 2,7-diF-4-MeQ) were all non-mutagenic in the Ames test. 7-F-4-MeQ was as highly mutagenic as, and 6-F-4-MeQ was less mutagenic than non-fluorinated 4-MeQ. Metabolic studies were also conducted with 4-MeQ, 2-F-4-MeQ, 6-F-4-MeQ, and 7-F-4-MeQ, using a liver microsomal enzyme fraction prepared from the 3-methylcholanthrene-treated rat. The HPLC analytical data showed that, although the metabolic patterns (hydroxylation at 4-methyl group as a main metabolic pathway and 3-hydroxylation as a minor pathway) of these four F-MeQs were similar to one another, only the 3-hydroxy metabolite of 2-F-4-MeQ was not produced under the present experimental conditions employed. These results suggest that fluorine-substitution at position 2 of 4-MeQ inhibited the formation of the enamine epoxide in the pyridine moiety and deprived this molecule of mutagenicity as in the case of quinoline. Copyright (C) 2000 Elsevier Science B.V.
- Kato, Taka-Aki,Hakura, Atsushi,Mizutani, Takaharu,Saeki, Ken-Ichi
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p. 173 - 182
(2007/10/03)
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- Rapid Side-chain Chlorination of Heterocyclic Compounds using Focused Microwave Irradiation
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Rapid chlorination of side-chain Me groups of substituted quinolines and 2-mercapto-5-methyl 1,3,4-oxadiazole/ thiadiazole is reported using sodium Hypochlorits under microwave irradiation.
- Kidwai, Mazaahir,Kohli, Seema,Kumar, Parven
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p. 586 - 587
(2007/10/03)
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- Oxiranes with quinolone substitution: Stereoselective synthesis and antiviral activity
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A series of new quinoline substituted oxiranes were synthesized by the reaction of 2-N-(chloroacetyl)-1-(4'-methyl-2'-quinolinyl) hydrazine and aromatic aldehydes. These compounds were tested against encephalomyocarditis virus (EMVC) and only two compounds exhibited protection against the virus.
- Kidwai,Kumar,Goel,Srivastava
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p. 871 - 874
(2007/10/03)
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