179943-57-8Relevant 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)
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.
Synthesis, structure-activity relationships and preliminary mechanism of action of novel water-soluble 4-quinolone-3-carboxamides as antiproliferative agents
Zhang, Zeyan,Xiao, Xingpeng,Su, Tong,Wu, Jinyi,Ren, Jianwei,Zhu, Jiongchang,Zhang, Xiaodong,Cao, Rihui,Du, Runlei
, p. 239 - 251 (2017)
A series of novel water-soluble 4-quinolone-3-carboxamides was prepared and evaluated as antiproliferative agents. Preliminary results indicated that most compounds tested in this study showed potent antiproliferative potencies against human tumor cell li
3-(Benzo[: D] thiazol-2-yl)-4-aminoquinoline derivatives as novel scaffold topoisomerase i inhibitor via DNA intercalation: Design, synthesis, and antitumor activities
Chen, Nan-Ying,Gu, Zi-Yu,Li, Xiao-Juan,Liao, Hao-Ran,Mo, Dong-Liang,Pan, Cheng-Xue,Su, Gui-Fa,Yuan, Jing-Mei,Zhang, Guo-Hai
, p. 11203 - 11214 (2020/07/15)
Twenty-seven 3-(benzo[d]thiazol-2-yl)-4-aminoquinoline derivatives have been designed and synthesized as topoisomerase I inhibitors. The in vitro anti-proliferation evaluation against four human cancer cell lines (MGC-803, HepG-2, T24, and NCI-H460) and one normal cell line (HL-7702) indicated that most of them exhibited potent cytotoxicity. Among them, 5a was identified as the most promising candidate with a low IC50 value of about 2.20 ± 0.14 and was selected for further exploration. Spectroscopic analyses and agarose-gel electrophoresis assays indicated that 5a could interact with DNA and strongly inhibit topoisomerase I (Topo I). Further screening of the Topo I activity of compounds 5b, 5c, 5e, 5f, 5h, 5i, 5j, 5l, and 5n suggested that some of the compounds might exert quite a different cytotoxicity profile to that of 5a. Molecular modeling studies confirmed that 5a adopts a unique mode to interact with DNA and Topo I. Other molecular mechanistic studies suggested that the treatment of MGC-803 cells with 5a induces S phase arrest, up-regulates the pro-apoptotic protein, down-regulates the anti-apoptotic protein, activates caspase-3, and subsequently induces mitochondrial dysfunction so as to induce cell apoptosis. The in vivo efficiency of 5a was also evaluated on MGC-803 xenograft nude mice and the relative tumor growth inhibition was 42.4percent at 12 mg kg-1 without an obvious loss in the body weight. This journal is
Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents
Alsayed, Shahinda S. R.,Beh, Chau Chun,Bishai, William R.,Foster, Neil,Gunosewoyo, Hendra,Lun, Shichun,Luna, Giuseppe,Payne, Alan D.
, p. 7523 - 7540 (2020/03/13)
Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) Mycobacterium tuberculosis (M. tb) strain. Naphthamide derivatives 13c and 13d were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds 8i and 18b had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tb strains. It is worth noting that the two most active compounds 13c and 13d also exhibited the highest selective activity towards DS, MDR and XDR M. tb strains over mammalian cells [IC50 (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five.
Antiviral activity of 4-oxoquinoline-3-carboxamide derivatives against bovine herpesvirus type 5
Pinto, Ana Maria V.,Leite, José Paulo G.,Marinho, Robson S.S.,Forezi, Luana da S.M.,Batalha, Pedro N.,Boechat, Fernanda da C.S.,Cunha, Anna C.,Silva, David O.,Gama, Ivson L.,Faro, Letícia V.,de Souza, Maria C.B.V.,Paix?o, Izabel Christina P.
, p. 13 - 20 (2020/10/21)
Background: Bovine herpesvirus type 5 is an important agent of meningoencephalitis in cattle and has been identified in outbreaks of bovine neurological disease in several Brazilian states. In recent years, oxoquinoline derivatives have become an important focus in antiviral drug research. Methods: The cytotoxicity and anti BoHV-5RJ42/01 activity of a set of synthetic 4-oxoquinoline derivatives 4a-k were assayed on Madin-Darby Bovine Kidney cell and antiviral activity by plaque reduction assay. Results: The most promising substance (4h) exhibited CC50 and EC50 values of 1,239 μM ±5.5 and 6.0 μM ±1.5, respectively, with an SI =206. Two other compounds 4j (CC50 = 35 μM ±2 and EC50 = 24 μM ±7.0) and 4k (CC50= 55 μM ±2 and EC50 = 24 μM ±5.1) presented similar inhibitory profile and selectivity indexes of 1.4 and 2.9, respectively. The results of the time-of-addition studies revealed expressive reduction of virus production (≥80%) in different stages of virus replication cycle except for compound 4h that slightly inhibited virus yield in the first 2 h post infection, but it showed expressive virus inhibition after this time. Conclusions: All three compounds slightly interact with the virus on the virucidal assay and they are not able to block virus attachment and penetration. Antiviral effect of oxoquinoline 4h was more prominent than acyclovir which leads us to suggest compound 4h as a promising molecule for further anti-BoHV-5 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.
Design, synthesis and biological evaluation of new quinoline derivatives as potential antitumor agents
Su, Tong,Zhu, Jiongchang,Sun, Rongqin,Zhang, Huihui,Huang, Qiuhua,Zhang, Xiaodong,Du, Runlei,Qiu, Liqin,Cao, Rihui
, p. 154 - 167 (2019/06/11)
A series of new quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 11p, 11s, 11v, 11x and 11y exhibited potent antiproliferative activity with IC50 value of lower than 10 μM against seven human tumor cell lines, and N-(3-methoxyphenyl)-7- (3-phenylpropoxy)quinolin-4-amine 11x was found to be the most potent antiproliferative agent against HCT-116, RKO, A2780 and Hela cell lines with an IC50 value of 2.56, 3.67, 3.46 and 2.71 μM, respectively. The antitumor efficacy of the representative compound 11x in mice was also evaluated, and the results showed that compound 11x effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 11x could inhibit colorectal cancer growth through ATG5-depenent autophagy pathway. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.
Synthesis and photodynamic effects of new porphyrin/4-oxoquinoline derivatives in the inactivation of S. aureus
Sagrillo, Fernanda Savacini,Dias, Cristina,Gomes, Ana T.P.C.,Faustino, Maria A.F.,Almeida, Adelaide,Gon?alves De Souza, Alan,Costa, Amanda Rodrigues Pinto,Boechat, Fernanda Da Costa Santos,Bastos Vieira De Souza, Maria Cecília,Neves, Maria G.P.M.S.,Cavaleiro, José A.S.
, p. 1910 - 1922 (2019/08/20)
New porphyrin/4-oxoquinoline conjugates were synthesized from the Heck coupling reaction of a β-brominated porphyrin with 1-allyl-4-oxoquinoline derivatives, followed by demetallation and deprotection affording the promising photosensitizers 9a-e. Singlet oxygen studies have demonstrated that all the porphyrin/4-oxoquinoline conjugates 9a-e were capable of producing cytotoxic species and found to be excellent photosensitizing agents in the inactivation of S. aureus by the antimicrobial photodynamic therapy (aPDT) protocol.
Fluorine walk: The impact of fluorine in quinolone amides on their activity against African sleeping sickness
Berninger, Michael,Erk, Christine,Fu?, Antje,Skaf, Joseph,Al-Momani, Ehab,Israel, Ina,Raschig, Martina,Güntzel, Paul,Samnick, Samuel,Holzgrabe, Ulrike
, p. 377 - 391 (2018/05/22)
Human African Trypanosomiasis, also known as African sleeping sickness, is caused by the parasitic protozoa of the genus Trypanosoma. If there is no pharmacological intervention, the parasites can cross the blood-brain barrier (BBB), inevitably leading to death of the patients. Previous investigation identified the quinolone amide GHQ168 as a promising lead compound having a nanomolar activity against T. b. brucei. Here, the role of a fluorine substitution at different positions was investigated in regard to toxicity, pharmacokinetics, and antitrypanosomal activity. This ‘fluorine walk’ led to new compounds with improved metabolic stability and consistent activity against T. b. brucei. The ability of the new quinolone amides to cross the BBB was confirmed using an 18F-labelled quinolone amide derivative by means of ex vivo autoradiography of a murine brain.
Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the γ-Aminobutyric Acid Type A Receptor (GABAAR) α6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability
Knutson, Daniel E.,Kodali, Revathi,Divovi?, Branka,Treven, Marco,Stephen, Michael R.,Zahn, Nicolas M.,Dobri?i?, Vladimir,Huber, Alec T.,Meirelles, Matheus A.,Verma, Ranjit S.,Wimmer, Laurin,Witzigmann, Christopher,Arnold, Leggy A.,Chiou, Lih-Chu,Ernst, Margot,Mihovilovic, Marko D.,Savi?, Miroslav M.,Sieghart, Werner,Cook, James M.
, p. 2422 - 2446 (2018/03/26)
Recent reports indicate that α6β2/3γ2 GABAAR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6β2/3γ2 GABAAR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABAAR α6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive α6β2/3γ2 GABAARs and were functionally silent at diazepam sensitive α1β2/3γ2 GABAARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABAAR α6β2/3γ2 subtypes.
