13161-87-0Relevant academic research and scientific papers
Reactivity of 9-aminoacridine drug quinacrine with glutathione limits its antiprion activity
?afa?ík, Martin,Mo?ko, Tibor,Zawada, Zbigniew,?afa?íková, Eva,Dra?ínsky, Martin,Holada, Karel,?ebestík, Jaroslav
, p. 932 - 942 (2017)
Quinacrine—the drug based on 9-aminoacridine—failed in clinical trials for prion diseases, whereas it was active in in vitro studies. We hypothesize that aromatic nucleophilic substitution at C9 could be contributing factor responsible for this failure be
Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials
Dodean, Rozalia A.,Kancharla, Papireddy,Li, Yuexin,Melendez, Victor,Read, Lisa,Bane, Charles E.,Vesely, Brian,Kreishman-Deitrick, Mara,Black, Chad,Li, Qigui,Sciotti, Richard J.,Olmeda, Raul,Luong, Thu-Lan,Gaona, Heather,Potter, Brittney,Sousa, Jason,Marcsisin, Sean,Caridha, Diana,Xie, Lisa,Vuong, Chau,Zeng, Qiang,Zhang, Jing,Zhang, Ping,Lin, Hsiuling,Butler, Kirk,Roncal, Norma,Gaynor-Ohnstad, Lacy,Leed, Susan E.,Nolan, Christina,Huezo, Stephanie J.,Rasmussen, Stephanie A.,Stephens, Melissa T.,Tan, John C.,Cooper, Roland A.,Smilkstein, Martin J.,Pou, Sovitj,Winter, Rolf W.,Riscoe, Michael K.,Kelly, Jane X.
, p. 3475 - 3502 (2019/03/29)
Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.
Determination of quinacrine dihydrochloride dihydrate stability and characterization of its degradants
Rotival, Romain,Espeau, Philippe,Corvis, Yohann,Guyon, Francois,Do, Bernard
experimental part, p. 3223 - 3232 (2012/06/15)
Although quinacrine dihydrochloride dihydrate is a widely used drug substance, a comprehensive determination of its stability profile is lacking. In this work, an integrative approach is implemented to determine the drug stability both in the solid state and aqueous solutions, identify the impurities that can be found in the active pharmaceutical ingredient, and evaluate the associated toxicity risks. Thermal analyses pointed out a two-step dehydration of the solid state. This phenomenon seems to be consistent with the organization of the water molecules in the crystal structure and results in the destruction of the lattice. Seven related compounds of quinacrine have been identified by liquid chromatography-ion trap mass spectrometry. The main thermal degradant both in the solid state and the solution corresponds to the N-deethyl compound, whereas quinacrine tertiary amine oxyde appears to be a signal impurity of oxidative stress in solution. Moreover, two photolytic impurities can be formed in solution either by aromatic amine cleavage or via O-demethylation. Additionally, using computational approaches, the analysis of the potential toxicity of the impurities compared with the parent compound one shows that ketone and O-demethyl derivatives may exhibit specific toxicity profiles.
Structure-trypanodical activity relationships
Bsiri,Johnson,Kayirere,Galy,Galy,Barbe,Osuna,Mesa-Valle,Castilla Calvente,Rodriguez-Cabezas
, p. 27 - 33 (2007/10/03)
A set of 9-thioalkylacridinones, has been prepared and investigated' in vitro' against T. cruzi. Structure-antiparasitic activity relationships are detailed with a view to identify the major structural parameters for the activity under consideration.
