83842-54-0Relevant articles and documents
Synthesis and characterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine and smooth muscle tissues
Becker,Antoine,Nguyen,Rigo,Cosgrove,Barnes,Dunne,Pirotte,Lebrun
, p. 375 - 385 (2001)
1. Original quinolinone derivatives structurally related to diazoxide were synthesized and their effects on insulin secretion from rat pancreatic islets and the contractile activity of rat aortic rings determined. 2. A concentration-dependent decrease of insulin release was induced by 6-chloro-2-methylquinolin4(1H)-one (HEI 713). The average IC50 values were 16.9±0.8 μM for HEI 713 and 18.4±2.2μM for diazoxide. 3. HEI 713 increased the rate of 86Rb outflow from perifused pancreatic islets. This effect persisted in the absence of external Ca2+ but was inhibited by glibenclamide, a KATP channel blocker. Inside-out patch-clamp experiments revealed that HEI 713 increased KATP channel openings. 4. HEI 713 decreased 45Ca outflow, insulin output and cytosolic free Ca2+ concentration in pancreatic islets and islet cells incubated in the presence of 16.7 or 20 mM glucose and extracellular Ca2+. The drug did not affect the K+(50 mM)-induced increase in 45Ca outflow. 5. In aortic rings, the vasorelaxant effects of HEI 713, less potent than diazoxide, were sensitive to glibenclamide and to the extracellular K+ concentration. 6. The drug elicited a glibenclamide-sensitive increase in 86Rb outflow from perifused rat aortic rings. 7. Our data describe an original compound which inhibits insulin release with a similar potency to diazoxide but which has fewer vasorelaxant effects. 8. Our results suggest that, in both aortic rings and islet tissue, the biological effects of HEI 713 mainly result from activation of KATP channels ultimately leading to a decrease in Ca2+ inflow.
Discovery, synthesis, and optimization of antimalarial 4(1 H)-quinolone-3-diarylethers
Nilsen, Aaron,Miley, Galen P.,Forquer, Isaac P.,Mather, Michael W.,Katneni, Kasiram,Li, Yuexin,Pou, Sovitj,Pershing, April M.,Stickles, Allison M.,Ryan, Eileen,Kelly, Jane Xu,Doggett, J. Stone,White, Karen L.,Hinrichs, David J.,Winter, Rolf W.,Charman, Susan A.,Zakharov, Lev N.,Bathurst, Ian,Burrows, Jeremy N.,Vaidya, Akhil B.,Riscoe, Michael K.
, p. 3818 - 3834 (2014/05/20)
The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.
4-Substituted Thioquinolines and Thiazoloquinolines: Potent, Selective, and Tween-80 invitro Dependent Families of Antitubercular Agents with Moderate invivo Activity
Escribano, Jaime,Rivero-Hernandez, Cristina,Rivera, Hilda,Barros, David,Castro-Pichel, Julia,Perez-Herran, Esther,Mendoza-Losana, Alfonso,Angulo-Barturen, Inigo,Ferrer-Bazaga, Santiago,Jimenez-Navarro, Elena,Ballell, Lluis
, p. 2252 - 2263 (2012/04/23)
Two new families of closely related selective, non-cytotoxic, and potent antitubercular agents were discovered: thioquinolines and thiazoloquinolines. The compounds were found to possess potent antitubercular properties invitro, an activity that is dependent on experimental conditions of MIC determination (resazurin test and the presence or absence of Tween-80). To clarify the therapeutic potential of these compound families, a medicinal chemistry effort was undertaken to generate a lead-like structure that would enable murine efficacy studies and help elucidate the invivo implications of the invitro observations. Although the final compounds showed only limited levels of systemic exposure in mice, modest levels of efficacy invivo at nontoxic doses were observed. Two new families: In this work we identified two new classes of potent antitubercular agents. Synthesis and analysis of the pharmacological properties of several analogues led to the discovery of potent and selective derivatives invitro, with moderate invivo activity.
