26893-12-9Relevant articles and documents
Hybrids of Imatinib with Quinoline: Synthesis, Antimyeloproliferative Activity Evaluation, and Molecular Docking
Bastos, Monica,Boechat, Nubia,Canzian, Henayle,Cunha, Anna,Dantas, Rafael,Hoelz, Lucas,Junior, Floriano,Marinho, Debora,Oliveira, Andressa,Pimentel, Luiz,Santos, Carine
, (2022/03/27)
Imatinib (IMT) is the first-in-class BCR-ABL commercial tyrosine kinase inhibitor (TKI). However, the resistance and toxicity associated with the use of IMT highlight the importance of the search for new TKIs. In this context, heterocyclic systems, such as quinoline, which is present as a pharmacophore in the structure of the TKI inhibitor bosutinib (BST), have been widely applied. Thus, this work aimed to obtain new hybrids of imatinib containing quinoline moieties and evaluate them against K562 cells. The compounds were synthesized with a high purity degree. Among the produced molecules, the inhibitor 4-methyl-N3-(4-(pyridin-3-yl)pyrimidin-2-yl)-N1-(quinolin-4-yl)benzene-1,3-diamine (2g) showed a suitable reduction in cell viability, with a CC50 value of 0.9 μM (IMT, CC50 = 0.08 μM). Molecular docking results suggest that the interaction between the most active inhibitor 2g and the BCR-ABL1 enzyme occurs at the bosutinib binding site through a competitive inhibition mechanism. Despite being less potent and selective than IMT, 2g is a suitable prototype for use in the search for new drugs against chronic myeloid leukemia (CML), especially in patients with acquired resistance to IMT.
Conjugate Addition Routes to 2-Alkyl-2,3-dihydroquinolin-4(1H)-ones and 2-Alkyl-4-hydroxy-1,2-dihydroquinoline-3-carboxylates
Kingsbury, Alex,Brough, Steve,McCarthy, Antonio Pedrina,Lewis, William,Woodward, Simon
supporting information, p. 1011 - 1017 (2019/12/27)
Under CuBr·SMe2/PPh3 catalysis (5/10 mol-%) RMgCl (R = Me, Et, nPr, CH=CH2, nBu, iBu, nC5H11, cC6H11, Bn, CH2Bn, nC11H23) readily (–78 °C) undergo 1,4-addition to Cbz or Boc protected quinolin-4(1H)-ones to provide 2-alkyl-2,3-dihydroquinolin-4(1H)-ones (14 examples, 54–99 % yield). Asymmetric versions require AlEt3 to Boc-protected ethyl 6-substituted 4(1H)-quinolone-3-carboxylates (6-R group = all halogens, n/i/t-alkyls, CF3) and provide 61–91 % yield, 30–86 % ee; any halogen, Me, or CF3 provide the highest stereoselectivities (76–86 % ee). Additions of AlMe3 or Al(nC8H17)3 provide ≈ 45 and ≈ 75 % ee on addition to the parent (6-R = H). Ligand (S)-(BINOL)P–N(CHPh2)(cC6H11) provides the highest ee values engendering addition to the Si face of the 4(1H)-quinolone-3-carboxylate. Allylation and deprotection of a representative 1,4-addition product example confirm the facial selectivity (X-ray crystallography).
Design, synthesis, in vitro and in silico studies of novel 4-oxoquinoline ribonucleoside derivatives as HIV-1 reverse transcriptase inhibitors
Forezi, Luana da S.M.,Ribeiro, Mariana M.J.,Marttorelli, Andressa,Abrantes, Juliana L.,Rodrigues, Carlos R.,Castro, Helena Carla,Souza, Thiago Moreno L.,Boechat, Fernanda da C.S.,de Souza, Alessandra M.T.,de Souza, Maria Cecília B.V.
, (2020/04/02)
Human immunodeficiency virus type 1 (HIV-1) is a public health problem that affects over 38 million people worldwide. Although there are highly active antiretroviral therapies, emergence of antiviral resistant strains is a problem which leads to almost a million death annually. Thus, the development of new drugs is necessary. The viral enzyme reverse transcriptase (RT) represents a validated therapeutic target. Because the oxoquinolinic scaffold has substantial biological activities, including antiretroviral, a new series of 4-oxoquinoline ribonucleoside derivatives obtained by molecular hybridization were studied here. All synthesized compounds were tested against human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), and 9a and 9d displayed the highest antiviral activities, with IC50 values of 1.4 and 1.6 μM, respectively. These compounds were less cytotoxic than AZT and showed CC50 values of 1486 and 1394 μM, respectively. Molecular docking studies showed that the most active compounds bound to the allosteric site of the enzyme, suggesting a low susceptibility to the development of antiviral resistance. In silico pharmacokinetic and toxicological evaluations reinforced the potential of the active compounds as anti-HIV candidates for further exploration. Overall, this work showed that compounds 9a and 9d are promising scaffold for future anti-HIV-1 RT drug design.
Green efficient synthesis method of quinolone compound
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Paragraph 0017; 0018, (2019/05/08)
The invention discloses a green efficient synthesis method of a quinolone compound. The method is as follows: Step 1, a dicarbonyl compound, triethyl orthoformate and an aniline compound react in theabsence of a solvent and a catalyst to obtain an enamine ester intermediate; and Step 2, the enamine ester intermediate is subjected to an intramolecular cyclization reaction under the action of a cyclization reagent diphenyl ether to obtain a quinolone parent ring compound. The purity of the product reaches up to 98.8%. the synthesis method of the invention has the following main beneficial effects: 1, the reaction in the Step 1 is efficient, and no catalyst or solvent is used so as to avoid generation of the three wastes and the yield is high; 2, the process in the step 2 is green, the cyclization reagent can be recycled and reused; and 3, the process is simple, the steps 1 and 2 can be carried out in the same reactor, and the quinolone compound is obtained after reaction and filtration.
4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation
Medapi, Brahmam,Suryadevara, Priyanka,Renuka, Janupally,Sridevi, Jonnalagadda Padma,Yogeeswari, Perumal,Sriram, Dharmarajan
, p. 1 - 16 (2015/09/02)
Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially underexploited drug targets in the field of antitubercular drug discovery. In the present study, we employed structural optimization of the reported GyrB inhibitor resulting in synthesis of a series of 46 novel quinoline derivatives. The compounds were evaluated for their in vitro Mycobacterium smegmatis GyrB inhibitory ability and Mycobacterium tuberculosis DNA supercoiling inhibitory activity. The antitubercular activity of these compounds was tested over Mtb H37Rv strain and their safety profile was checked against mouse macrophage RAW 264.7 cell line. Among all, three compounds (23, 28, and 53) emerged to be active displaying IC50 values below 1 μM against Msm GyrB and were found to be non-cytotoxic at 50 μM concentration. Compound 53 was identified to be potent GyrB inhibitor with 0.86 ± 0.16 μM and an MIC (minimum inhibitory concentration) of 3.3 μM. The binding affinity of this compound towards GyrB protein was analysed by differential scanning fluorimetry which resulted in a positive shift of 3.3 °C in melting temperature (Tm) when compared to the native protein thereby reacertaining the stabilization effect of the compound over protein.
How to convert a walk-in hood into a manufacturing facility: Demonstration of a continuous, high-temperature cyclization to process solids in flow
White, Timothy D.,Alt, Charles A.,Cole, Kevin P.,Groh, Jennifer McClary,Johnson, Martin D.,Miller, Richard D.
, p. 1482 - 1491 (2015/02/19)
An intramolecular thermal cyclization protocol was developed in a flow reactor to take advantage of the high pressures and temperatures that are easily obtained in small scale autoclave reactors that have been modified to handle slurries. This reactor was equipped with a fill/empty pumping system to enable easy and nearly complete transfer of slurries. The reaction conditions were designed to take advantage of the insolubility of the product in order to separate it from residual starting material by filtration after short reaction times. Recycling of the filtrate maximized the yield and throughput while minimizing decomposition. Recycles were accomplished using a strip to dryness protocol that was easily performed in a rotary evaporator. This new equipment set was designed with lab-hood manufacturing in mind, a minimized footprint, and the system was completely automated for charging, emptying, rinsing, and reacting. Additional efforts for quick screening and alternate modes of addition were also investigated.
Synthesis and biological evaluation of 4-oxoquinoline-3-carboxamides derivatives as potent anti-fibrosis agents
Zhu, Jun,He, Lin,Ma, Liang,Wei, Zhe,He, Jiqiang,Yang, Zhuang,Pu, Yuzhi,Cao, Dong,Wu, Yuzhe,Xiang, Mingli,Peng, Aihua,Wei, Yuquan,Chen, Lijuan
supporting information, p. 5666 - 5670 (2015/01/08)
Thirty-one 4-oxoquinoline-3-carboxamides derivatives were synthesized and evaluated for their anti-fibrotic activities by the inhibition of TGF-β1-induced total collagen accumulation and anti-inflammatory activities by the inhibition of LPS-stimulated TNF-α production. Among them, three compounds (10a, 10l and 11g) exhibited potent inhibitory effects on both TGF-β1-induced total collagen accumulation and LPS-stimulated TNF-α production. Furthermore, oral administrations of 10l at a dose of 20 mg/kg/day for 4 weeks effectively alleviated lung inflammation and injury, and decreased lung collagen accumulation in bleomycin-induced pulmonary fibrosis model. Histopathological evaluation of lung tissue confirmed 10l as a potential, orally active agent for the treatment of pulmonary fibrosis.
Structural optimization of quinolon-4(1 H)-imines as dual-stage antimalarials: Toward increased potency and metabolic stability
Ressurrei??o, Ana S.,Gon?alves, Daniel,Sitoe, Ana R.,Albuquerque, Ine?s S.,Gut, Jiri,Góis, Ana,Gon?alves, Lídia M.,Bronze, Maria R.,Hanscheid, Thomas,Biagini, Giancarlo A.,Rosenthal, Philip J.,Prude?ncio, Miguel,O'Neill, Paul,Mota, Maria M.,Lopes, Francisca,Moreira, Rui
, p. 7679 - 7690 (2013/11/06)
Discovery of novel effective and safe antimalarials has been traditionally focused on targeting erythrocytic parasite stages that cause clinical symptoms. However, elimination of malaria parasites from the human population will be facilitated by intervent
A small-molecule inhibitor of nipah virus envelope protein-mediated membrane fusion
Niedermeier, Sabine,Singethan, Katrin,Rohrer, Sebastian G.,Matz, Magnus,Kossner, Markus,Diederich, Sandra,Maisner, Andrea,Schmitz, Jens,Hiltensperger, Georg,Baumann, Knut,Holzgrabe, Ulrike,Schneider-Schaulies, Jurgen
supporting information; experimental part, p. 4257 - 4265 (2010/03/04)
Nipah virus (NiV), a highly pathogenic paramyxovirus, causes respiratory disease in pigs and severe febrile encephalitis in humans with high mortality rates. On the basis of the structural similarity of viral fusion (F) proteins within the family Paramyxoviridae, we designed and tested 18 quinolone derivatives in a NiV and measles virus (MV) envelope protein-based fusion assay beside evaluation of cytotoxicity. We found five compounds successfully inhibiting NiV envelope protein-induced cell fusion. The most active molecules (19 and 20), which also inhibit the syncytium formation induced by infectious NiV and show a low cytotoxicity in Vero cells, represent a promising lead quinolone-type compound structure. Molecular modeling indicated that compound 19 fits well into a particular protein cavity present on the NiV F protein that is important for the fusion process. 2009 American Chemical Society.
Investigations on the 4-quinolone-3-carboxylic acid motif. 2. Synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo
Pasquini, Serena,Botta, Lorenzo,Semeraro, Teresa,Mugnaini, Claudia,Ligresti, Alessia,Palazzo, Enza,Maione, Sabatino,Di Marzo, Vincenzo,Corelli, Federico
experimental part, p. 5075 - 5084 (2009/07/25)
Quinolone-3-carboxamides 11 bearing at position 5, 6, 7, or 8 diverse substituents such as halides, alkyl, aryl, alkoxy, and aryloxy groups differing in their steric/electronic properties, were prepared. The new compounds were tested in vitro for CB1 and
