71083-04-0Relevant articles and documents
Defined concatenated α6α1β3γ2 GABAA receptor constructs reveal dual action of pyrazoloquinolinone allosteric modulators
Simeone,Iorio,Siebert,Rehman,Schnürch,Mihovilovic,Ernst
, p. 3167 - 3178 (2019/06/17)
Pyrazoloquinolinones (PQs) have been extensively studied as modulators of GABAA receptors with different subunit composition, exerting modulatory effects by binding at α+/β- interfaces of GABAA receptors. PQs with a substituent in position R7 have been reported to preferentially modulate α6- subunit containing GABAA receptors which are mostly expressed in the cerebellum but were also found in the olfactory bulb, in the cochlear nucleus, in the hippocampus and in the trigeminal sensory pathway. They are considered potentially interesting in the context of sensori-motor gating deficits, depressive-like behavior, migraine and orofacial pain. Here we explored the option to modify the lead ligands’ R7 position. In the compound series we observed two different patterns of allosteric modulation in recombinantly expressed α6β3γ2 receptors, namely monophasic and biphasic positive modulation. In the latter case the additional phase occurred in the nanomolar range, while all compounds displayed robust modulation in the micromolar range. Nanomolar, near silent binding has been reported to occur at benzodiazepine binding sites, but was not investigated at the diazepam insensitive α6+/γ2- interface. To clarify the mechanism underlying the biphasic effect we tested one of the compounds in concatenated receptors. In these constructs the subunits are covalently linked, allowing to form either the α6+/γ2- interface, or the α6+/β3- interface, to study the resulting modulation. With this approach we were able to ascribe the nanomolar modulation to the α6+/γ2- interface. While not all compounds display the nanomolar phase, the strong modulation at the α6+/β3 interface proved to be tolerant for all tested R7 groups. This provides the future option to introduce e.g. isotope labelled or fluorescent moieties or substituents that enhance solubility and bioavailability.
Structural development of a type-1 ryanodine receptor (RyR1) Ca2+-release channel inhibitor guided by endoplasmic reticulum Ca2+ assay
Mori, Shuichi,Iinuma, Hiroto,Manaka, Noriaki,Ishigami-Yuasa, Mari,Murayama, Takashi,Nishijima, Yoshiaki,Sakurai, Akiko,Arai, Ryota,Kurebayashi, Nagomi,Sakurai, Takashi,Kagechika, Hiroyuki
, p. 837 - 848 (2019/07/12)
Type-1 ryanodine receptor (RyR1) is a calcium-release channel localized on sarcoplasmic reticulum (SR) of the skeletal muscle, and mediates muscle contraction by releasing Ca2+ from the SR. Genetic mutations of RyR1 are associated with skeletal muscle diseases such as malignant hyperthermia and central core diseases, in which over-activation of RyR1 causes leakage of Ca2+ from the SR. We recently developed an efficient high-throughput screening system based on the measurement of Ca2+ in endoplasmic reticulum, and used it to identify oxolinic acid (1) as a novel RyR1 channel inhibitor. Here, we designed and synthesized a series of quinolone derivatives based on 1 as a lead compound. Derivatives bearing a long alkyl chain at the nitrogen atom of the quinolone ring and having a suitable substituent at the 7-position of quinolone exhibited potent RyR1 channel-inhibitory activity. Among the synthesized compounds, 14h showed more potent activity than dantrolene, a known RyR1 inhibitor, and exhibited high RyR1 selectivity over RyR2 and RyR3. These compounds may be promising leads for clinically applicable RyR1 channel inhibitors.
Novel hybrids of metronidazole and quinolones: Synthesis, bioactive evaluation, cytotoxicity, preliminary antimicrobial mechanism and effect of metal ions on their transportation by human serum albumin
Cui, Sheng-Feng,Peng, Li-Ping,Zhang, Hui-Zhen,Rasheed, Syed,Vijaya Kumar, Kannekanti,Zhou, Cheng-He
, p. 318 - 334 (2014/10/15)
A novel series of hybrids of metronidazole and quinolones as antimicrobial agents were designed and synthesized. Most prepared compounds exhibited good or even stronger antimicrobial activities in comparison with reference drugs. Furthermore, these highly active metronidazole-quinolone hybrids showed appropriate ranges of pKa, log P and aqueous solubility to pharmacokinetic behaviors and no obvious toxicity to A549 and human hepatocyte LO2 cells. Their competitive interactions with metal ions to HSA revealed that the participation of Mg2+ ion in compound 7d-HSA association could result in a concentration increase of free compound 7d. Molecular modeling and experimental investigation of compound 7d with DNA suggested that possible antibacterial mechanism might be in relation with multiple binding sites between bioactive molecules and topo IV-DNA complex.
Synthesis and biological evaluation of a class of quinolone triazoles as potential antimicrobial agents and their interactions with calf thymus DNA
Cui, Sheng-Feng,Ren, Yu,Zhang, Shao-Lin,Peng, Xin-Mei,Damu, Guri L.V.,Geng, Rong-Xia,Zhou, Cheng-He
, p. 3267 - 3272 (2013/06/27)
A novel series of quinolone triazoles were synthesized and characterized by IR, NMR, MS and HRMS spectra. All the newly prepared compounds were screened for their antimicrobial activities against seven bacteria and four fungi. Bioactive assay manifested that most of new compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains including multi-drug resistant MRSA in comparison with reference drugs Norfloxacin, Chloromycin and Fluconazole. The preliminary interactive investigations of compound 6b with calf thymus DNA by fluorescence and UV-vis spectroscopic methods revealed that compound 6b could effectively intercalate DNA to form compound 6b-DNA complex which might block DNA replication and thus exert its antimicrobial activities.
Lead optimization of 3-carboxyl-4(1 H)-quinolones to deliver orally bioavailable antimalarials
Zhang, Yiqun,Clark, Julie A.,Connelly, Michele C.,Zhu, Fangyi,Min, Jaeki,Guiguemde, W. Armand,Pradhan, Anupam,Iyer, Lalitha,Furimsky, Anna,Gow, Jason,Parman, Toufan,El Mazouni, Farah,Phillips, Margaret A.,Kyle, Dennis E.,Mirsalis, Jon,Guy, R. Kiplin
, p. 4205 - 4219 (2012/07/02)
Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.
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.
QUINOLINE DERIVATIVES AS CASPASE-3 INHIBITOR, PREPARATION PROCESS FOR THE SAME AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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Page/Page column 60-61, (2008/12/07)
Provided is a quinoline derivative represented by the following Formula (1) for use in treating a caspase- mediated disease by inhibition of caspase-3 activity. Further provided are a method for preparing the quinoline derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same.
Evaluation of 3-carboxy-4(1H)-quinolones as inhibitors of human protein kinase CK2
Golub, Andriy G.,Yakovenko, Olexander Ya.,Bdzhola, Volodymyr G.,Sapelkin, Vladislav M.,Zien, Piotr,Yarmoluk, Sergiy M.
, p. 6443 - 6450 (2007/10/03)
Due to the emerging role of protein kinase CK2 as a molecule that participates not only in the development of some cancers but also in viral infections and inflammatory failures, small organic inhibitors of CK2, besides application in scientific research, may have therapeutic significance. In this paper, we present a new class of CK2 inhibitors-3-carboxy-4(1H)-quinolones. This class of inhibitors has been selected via receptor-based virtual screening of the Otava compound library. It was revealed that the most active compounds, 5,6,8-trichloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7) (IC 50 = 0.3 μM) and 4-oxo-1,4-dihydrobenzo[h]quinoline-3-carboxylic acid (9) (IC50 = 1 μM), are ATP competitive (Ki values are 0.06 and 0.28 μM, respectively). Evaluation of the inhibitors on seven protein kinases shows considerable selectivity toward CK2. According to theoretical calculations and experimental data, a structural model describing the key features of 3-carboxy-4(1H)-quinolones responsible for tight binding to CK2 active site has been developed.
