- Synthesis, Structure-Activity Relationship, and Antimalarial Efficacy of 6-Chloro-2-arylvinylquinolines
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There is an urgent need to develop new efficacious antimalarials to address the emerging drug-resistant clinical cases. Our previous phenotypic screening identified styrylquinoline UCF501 as a promising antimalarial compound. To optimize UCF501, we herein report a detailed structure-activity relationship study of 2-arylvinylquinolines, leading to the discovery of potent, low nanomolar antiplasmodial compounds against a Plasmodium falciparum CQ-resistant Dd2 strain, with excellent selectivity profiles (resistance index 200). Several metabolically stable 2-arylvinylquinolines are identified as fast-acting agents that kill asexual blood-stage parasites at the trophozoite phase, and the most promising compound 24 also demonstrates transmission blocking potential. Additionally, the monophosphate salt of 24 exhibits excellent in vivo antimalarial efficacy in the murine model without noticeable toxicity. Thus, the 2-arylvinylquinolines represent a promising class of antimalarial drug leads.
- Huang, Guang,Murillo Solano, Claribel,Melendez, Joel,Shaw, Justin,Collins, Jennifer,Banks, Robert,Arshadi, Arash Keshavarzi,Boonhok, Rachasak,Min, Hui,Miao, Jun,Chakrabarti, Debopam,Yuan, Yu
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p. 11756 - 11785
(2020/11/26)
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- Syntheses and evaluation of new Quinoline derivatives for inhibition of hnRNP K in regulating oncogene c-myc transcription
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Aberrant overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key feature in oncogenesis and progression of many human cancers. hnRNP K has been found to be a transcriptional activator to up-regulate c-myc gene transcription, a critical proto-oncogene for regulation of cell growth and differentiation. Therefore, down-regulation of c-myc transcription by inhibiting hnRNP K through disrupting its binding to c-myc gene promoter is a potential approach for cancer therapy. In the present study, we synthesized and screened a series of Quinoline derivatives and evaluated their binding affinity for hnRNP K. Among these derivatives, (E)-1-(4-methoxyphenyl)-3-(4-morpholino-6-nitroquinolin-2-yl)prop-2-en-1-one (compound 25) was determined to be the first-reported hnRNP K binding ligand with its KD values of 4.6 and 2.6 μM measured with SPR and MST, respectively. Subsequent evaluation showed that the binding of compound 25 to hnRNP K could disrupt its unfolding of c-myc promoter i-motif, resulting in down-regulation of c-myc transcription. Compound 25 showed a selective anti-proliferative effect on human cancer cell lines with IC50 values ranged from 1.36 to 3.59 μM. Compound 25 exhibited good tumor growth inhibition in a Hela xenograft tumor model, which might be related to its binding with hnRNP K. These findings illustrated that inhibition of DNA-binding protein hnRNP K by compound 25 could be a new and selective strategy of regulating oncogene transcription instead of targeting promoter DNA secondary structures such as G-quadruplexes or i-motifs.
- Shu, Bing,Zeng, Ping,Kang, Shuangshuang,Li, Peng-Hui,Hu, Dexuan,Kuang, Guotao,Cao, Jiaojiao,Li, Xiaoya,Zhang, Meiling,An, Lin-Kun,Huang, Zhi-Shu,Li, Ding
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- Synthesis and identification of quinoline derivatives as topoisomerase I inhibitors with potent antipsoriasis activity in an animal model
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Psoriasis is a chronic inflammatory and immune-mediated skin disease. Although certain agents have shown clinical success in treating psoriasis, development of safe and effective strategies for the treatment of this condition remains important. Research suggests that DNA topoisomerase I (Topo I)inhibitors may have potent psoriasis-ameliorating effects. Here, 25 quinoline derivatives were synthesized and identified as Topo I inhibitors. These compounds inhibited the 12–O–tetradecanoylphorbol-13-acetate-induced mouse ear inflammation. The most potent analogs, 5i and 5l, suppressed the expression of inflammatory cytokines in lipopolysaccharide-stimulated HaCaT cells. Additionally, the lead compounds significantly improved imiquimod-induced psoriasis-like inflammation in mice. Moreover, the expression levels of cytokines and inflammatory mediators, such as interleukin (IL)-17A, IL-22, IL-23, nuclear factor-κB subunit p65, tumor necrosis factor-α, and interferon-γ, were dramatically inhibited in the dorsal skin of 5i- and 5l-treated mice. These findings indicate that the inhibition of Topo I activity may potentially be an effective strategy for psoriasis treatment.
- Zhang, Wen-Jin,Li, Peng-Hui,Zhao, Min-Cong,Gu, Yao-Hao,Dong, Chang-Zhi,Chen, Hui-Xiong,Du, Zhi-Yun
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- NEW TARGETED CYTOTOXIC ISOCOMBRETAQUINOLINE DERIVATIVES AND CONJUGATES THEREOF
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The present invention is directed to novel natural product-derived combretastatin- based compounds useful as payloads in drug-conjugates constructs with cell target binding moieties (CTBM) and payload-linker compounds useful in connection with drug conjugates. The present invention further relates to new isoNH2CombretaQuinoline compositions including the aforementioned payloads, payload-linkers and drug conjugates, and methods for using these payloads, payload-linkers and drug conjugates, to treat pathological conditions including cancer.
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Paragraph 00131
(2018/10/25)
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- New insights into the SAR and drug combination synergy of 2-(quinolin-4-yloxy)acetamides against Mycobacterium tuberculosis
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2-(Quinolin-4-yloxy)acetamides have been described as potent and selective in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Herein, a new series of optimized compounds were found to demonstrate highly potent antitubercular activity, with minimum inhibitory concentration (MIC) values against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains in the submicromolar range. Furthermore, the most active compounds had no apparent toxicity to mammalian cells, and they showed intracellular activities similar to those of isoniazid and rifampin in a macrophage model of Mtb infection. Use of the checkerboard method to investigate the association profiles of lead compounds with first- and second-line antituberculosis drugs showed that 2-(quinolin-4-yloxy)acetamides have a synergistic effect with rifampin. Ultimately, the good permeability, moderate rates of metabolism and low risk of drug-drug interactions displayed by some of the synthesized compounds indicate that 2-(quinolin-4-yloxy)acetamides may yield candidates to use in the development of novel alternative therapeutics for tuberculosis treatment.
- Giacobbo, Bruno Couto,Pissinate, Kenia,Rodrigues-Junior, Valnês,Villela, Anne Drumond,Grams, Estêv?o Silveira,Abbadi, Bruno Lopes,Subtil, Fernanda Teixeira,Sperotto, Nathalia,Trindade, Rogério Valim,Back, Davi Fernando,Campos, Maria Martha,Basso, Luiz Augusto,Machado, Pablo,Santos, Diógenes Santiago
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p. 491 - 501
(2016/12/09)
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- Synthesis and antitubercular and antibacterial activity of some active fluorine containing quinoline–pyrazole hybrid derivatives
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In an attempt to develop newer antitubercular and antibacterial agents against the increasing bacterial resistance, we have designed new quinoline–pyrazole analogs (8a–u) following the molecular hybridization approach. The structure of one of the final compounds, 8a was unambiguously confirmed by single crystal X-ray diffraction (SC-XRD) analysis. The target compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis and antibacterial activity against three common pathogenic bacterial strains. Four derivatives (8b, 8c, 8j and 8o) displayed significant antitubercular activity. The compounds derived from 8-trifluoromethylquinoline and 6-fluoroquinoline scaffolds with halogen substitution on the pyrazole ring exhibited superior inhibition activity than corresponding 6-methoxyquinoline analogs. The cytotoxic studies revealed that the active compounds are nontoxic to normal Vero cell lines with selectivity index values ≥10, which indicate the suitability of these compounds for further drug development. The in silico molecular docking study demonstrated strong binding affinity of the compounds with the target enzymes (InhA, CYP121 and TMPK) of M. tuberculosis. Further, the in vitro antibacterial activity of compounds 8b, 8c, 8d and 8g is comparable with that of the reference drug, Ciprofloxacin.
- Nayak, Nagabhushana,Ramprasad, Jurupula,Dalimba, Udayakumar
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- Design, synthesis and biological evaluation of 2-substituted quinolines as potential antileishmanial agents
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An analogous library of 2-substituted quinoline compounds was synthesized with the aim to identify a potential drug candidate to treat visceral leishmaniasis. These molecules were tested for their in vitro and in vivo biological activity against Leishmania donovani. Metabolic stability of these compounds was also improved through the introduction of halogen substituents. Compound (26g), found to be the most active; exhibited an IC50 value of 0.2 μM and >180 fold selectivity. The hydrochloride salt of (26g) showed 84.26 ± 4.44 percent inhibition at 50 mg/kg × 5 days (twice daily, oral route) dose in L. donovani/hamster model. The efficacy was well correlated with the PK data observed which indicating that the compound is well distributed.
- Gopinath, Vadiraj S.,Pinjari, Jakir,Dere, Ravindra T.,Verma, Aditya,Vishwakarma, Preeti,Shivahare, Rahul,Moger, Manjunath,Kumar Goud, Palusa Sanath,Ramanathan, Vikram,Bose, Prosenjit,Rao,Gupta, Suman,Puri, Sunil K.,Launay, Delphine,Martin, Denis
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supporting information
p. 527 - 536
(2013/10/22)
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- N1-{4-[(10S)-Dihydroartemisinin-10-oxyl]}phenylmethylene-N 2-(2-methylquinoline-4-yl)hydrazine derivatives as antiplasmodial falcipain-2 inhibitors
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A series of N1-{4-[(10S)-dihydroartemisinin- 10-oxyl]}phenylmethylene-N2-(2-methylquinoline-4-yl) hydrazine derivatives 9a-9n possessing 4-quinolylhydrazone and artemisinin cores were herein synthesized and evaluated for their activities against cysteine protease falcipain- 2 of Plasmodium falciparum. The structures were clearly confirmed by elemental analysis, 1H NMR, and mass spectra. The pharmacological results indicated that all compounds showed excellent activity against recombinant falcipain-2 (IC50 = 0.15-2.28 μM). The best one of this series was compound 9d (IC50 = 0.15 μM). The molecular docking results showed that the compound 9d made close contact with the key active site of cysteine protease falcipain-2.
- Luo, Wei,Liu, Yang,Wang, Jian,Guo, Chun,Lu, Wei-Qiang,Cui, Kun-Qiang
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p. 3073 - 3079,7
(2020/08/20)
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- Design, synthesis and antiproliferative activity of novel 2-substituted-4-amino-6-halogenquinolines
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Two series of novel 2-substituted-4-amino-6-halogenquinolines 8a-l and 13a-h were designed, synthesized and evaluated for their antiproliferative activity against H-460, HT-29, HepG2 and SGC-7901 cancer cell lines in vitro. The pharmacological results indicated that most compounds with 2-arylvinyl substituents exhibited good to excellent antiproliferative activity. Among them, compound 8e was a considered promising lead for further structural modifications with IC50 values of 0.03 μM, 0.55 μM, 0.33 μM and 1.24 μM, which was 2.5- to 186-fold more active than gefitinib and compound 1.
- Jiang, Nan,Zhai, Xin,Li, Ting,Liu, Difa,Zhang, Tingting,Wang, Bin,Gong, Ping
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experimental part
p. 5870 - 5881
(2012/09/22)
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- Design, synthesis and cytotoxicity of novel 2-arylvinyl-4- aminoquinoline derivatives
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With an aim to develop promising anti-tumor agents, a novel series of 2-arylvinyl-4-aminoquinoline derivatives were designed, synthesized and evaluated for their cytotoxicity against H-460, HT-29, HepG2 and SGC-7901 cell lines in vitro. The pharmacological results indicated that most compounds were more potent than the positive controls, especially compounds 8, 14 and 16 with IC50 values ranging from 0.05 to 0.85 μM against all tested cell lines respectively, which were 5.7- to 112-fold better than Iressa. The most active compound 14 (IC50 values of 0.05, 0.25, 0.16, 0.68 μM), bearing 4-fluorostyryl at C-2 position and 3-(dimethylamino)-1-propylamino at C-4 position, showed great promise as a lead for the development of more effective quinoline analogues.
- Jiang, Nan,Zhai, Xin,Chen, Zhichao,Liang, Chuang,Sun, Chao,Han, Jing,Gong, Ping
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p. 659 - 664
(2012/06/29)
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