- Design and synthesis of the novel, selective WZ4002 analogue as EGFR-L858R/T790M tyrosine kinase inhibitors for targeted drug therapy in non-small-cell lung cancer (NSCLC)
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To conquer the drug-resistance of first-generation EGFR (epidermal growth factor receptor) kinase inhibitors and second-generation inhibitors’ non-selective toxicities in Non-Small Cell Lung Cancer (NSCLC) patients, a series of WZ4002 derivatives (6–46) were discovered as novel double mutant EGFR-L858R/T790M TK inhibitors. This objective was attained by employing structure-based drug design and traditional optimization strategies based on the WZ4002 scaffold. Among the synthesized compounds, representative compounds 8 and 38 displayed significant anti-proliferative activity on the Gefitinib-resistant cell line NCI-H1975, with an IC50 value of 0.179 μM and 0.173 μM, respectively. Also, these compounds exhibited moderate anti-proliferative activity against the A549 cell, with an IC50 of 0.550 μM and 0.528 μM respectively, suggesting their improved selectivity over the mutant EGFR-L858R/T790M. Excitingly, both these compounds showed significant inhibition of the double mutant EGFR-L858R/T790M TK with an IC50 value of 0.0063 μM and 0.0060 μM, respectively. The IC50 values of both the promising compounds against the HepG2 cell line were more than 1 μM, indicating safety for normal cells. Covalent docking and MD simulation further confirm their irreversible binding mode with the target protein. These results demonstrate that compounds 8 and 38 would be promising lead compound-targeting double mutant EGFR-L858R/T790M TK.
- Ahmad, Iqrar,Belamkar, Sateesh,Kundu, Chanakya Nath,Nayak, Deepika,Patel, Harun,Patil, Chandragauda,Pawara, Rahul,Surana, Sanjay
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- The fight against the influenza A virus H1N1: Synthesis, molecular modeling, and biological evaluation of benzofurazan derivatives as viral RNA polymerase inhibitors
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The influenza RNA polymerase complex, which consists of the three subunits PA, PB1, and PB2, is a promising target for the development of new antiviral drugs. A large library of benzofurazan compounds was synthesized and assayed against influenza virus A/WSN/33 (H1N1). Most of the new derivatives were found to act by inhibiting the viral RNA polymerase complex through disruption of the complex formed between subunits PA and PB1. Docking studies were also performed to elucidate the binding mode of benzofurazans within the PB1 binding site in PA and to identify amino acids involved in their mechanism of action. The predicted binding pose is fully consistent with the biological data and lays the foundation for the rational development of more effective PA-PB1 inhibitors. In the fight against influenza virus A/WSN/33 (H1N1), the PA-PB1 protein-protein interaction is emerging as a new drug target. To identify small molecules able to inhibit the viral RNA polymerase complex, the benzofurazan scaffold was explored by synthesizing a large library of derivatives. Some compounds showed high anti-H1N1 activity and emerged as effective inhibitors of the PA-PB1 interaction, with IC50 values in the micromolar range. Copyright
- Pagano, Mafalda,Castagnolo, Daniele,Bernardini, Martina,Fallacara, Anna Lucia,Laurenzana, Ilaria,Deodato, Davide,Kessler, Ulrich,Pilger, Beatrice,Stergiou, Lilli,Strunze, Stephan,Tintori, Cristina,Botta, Maurizio
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p. 129 - 150
(2014/01/17)
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- NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE and INFLAMMATORY DISEASES
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The present invention relates to compounds of formula (I) that are inhibitors of PDElA, a phosphodiesterase that is involved in the modulation of the degradation of cartilage, joint degeneration and diseases involving such degradation and/or inflammation.
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Page/Page column 67
(2008/12/05)
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- Partial structures of ketoconazole as modulators of the large conductance calcium-activated potassium channel (BKCa)
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A series of partial structures of ketoconazole has been synthesized and tested for activity on the large conductance calcium-activated potassium channel (BK) in bovine smooth muscle cells. This has provided openers and blockers of the channel. The results suggest that the phenyl and phenoxy moieties are important for interaction with BK, whereas the imidazole group is unimportant. The properties of the phenoxy moiety seem to determine whether the compounds act to open or block the channel.
- Power, Eoin C.,Ganellin, C. Robin,Benton, David C.H.
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p. 887 - 890
(2007/10/03)
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- Antifungal azole derivatives having a fluorinated vinyl group and process for preparing same
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An antifungal compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein: X is CH or N; Y is O, R1and R2are each independently F or Cl; R3is a thiophenyl, naphthyl, or phenyl group, the phenyl group being optionally substituted with one or more substituents selected from the group consisting of C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, methylenedioxy and halogen; and R4is H or trifluoromethyl.
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- Synthesis and antifungal activity of structural analogues of bifonazole and ketoconazole
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The synthesis and antifungal activities of the cis- and trans-1-acetyl-4-[4-[[2-(1,1'-biphenyl-4-yl)-2-(1H-imidazol-l-ylmethyl )-1,3-dioxolan-4-yl]-methoxy]phenyl]piperazines 3 and 4 are reported. Stereochemical assignments to diastereomeric pairs of cis/trans isomers were made on the basis of 1H and 13C-NMR data. Among test derivatives the best activity was shown by the benzoyl esters of the cis- and trans-[2-(1,1'-biphenyl-4-yl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan- 4-yl]methanols 9 and 10.
- Stefancich,Artico,Ortar,Silvestri,Simonetti,Apuzzo,Artico
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p. 687 - 694
(2007/10/02)
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- 2-Aryl-1-(imidazol-1-yl)-8-(4-piperazin-1-ylphenoxy) octan-2-ol antifungal agents
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A series of novel 2-aryl-1-(imidazol-1-yl)-8-(4-piperazin-1-ylphenoxy)octan-2-ol derivatives has been prepared, including their pharmaceutically acceptable acid addition salts. These particular compounds are useful in therapy as antifungal agents for the treatment of various topical, mucosal and systemic fungal infections in animals, including humans. Preferred member compounds include 2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-8-[4-ethylpiperazin-1-yl)phenoxy]octan-2-ol, 2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-8-[4-(4-n-propylpiperazin-1-yl)phenoxy]octan-2-ol and 2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-8-[4-(4-isopropylpiperazin-1-yl)phenoxy]octan-2-ol, respectively. Methods for preparing these compounds from known starting materials are provided.
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- Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles
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Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles and 1H-1,2,4-triazoles useful as antifungal and antibacterial agents.
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