958457-41-5Relevant articles and documents
Scalable Multigram Syntheses of Antimalarial 4(1H)-Quinolones ELQ-300 and P4Q-391
Namelikonda, Niranjan K.,Monastyrskyi, Andrii,Manetsch, Roman
, p. 3328 - 3334 (2017/06/29)
Antimalarial compounds ELQ-300 and P4Q-391 are highly potent against the blood and the liver stages of the Plasmodium parasite and also possess potent transmission-blocking activity. Gram amounts of these two compounds were required for extensive assessment of in vivo efficacy, pharmacokinetics, and safety. Several deficiencies existed in the original synthetic routes of ELQ-300 and P4Q-391 including reliance on toxic heavy-metal reagents, harsh reaction conditions, and several low-yielding steps. Herein, we report the development of two alternative syntheses, which are reliable, high yielding, scalable, and have the potential to become a route of choice at process scale.
Metal-free arylation of ethyl acetoacetate with hypervalent diaryliodonium salts: An immediate access to diverse 3-aryl-4(1 H)-quinolones
Monastyrskyi, Andrii,Namelikonda, Niranjan K.,Manetsch, Roman
, p. 2513 - 2520 (2015/03/18)
A clean arylation protocol of ethyl acetoacetate was developed using hypervalent diaryliodonium salts under mild and metal-free conditions. The scope of the reaction, using symmetric and unsymmetric iodonium salts with varying sterics and electronics, was examined. Further, this method has been applied for the synthesis of antimalarial compound ELQ-300, which is currently in preclinical development.
Optimization of 1,2,3,4-tetrahydroacridin-9(10 H)-ones as antimalarials utilizing structure-activity and structure-property relationships
Cross, R. Matthew,Maignan, Jordany R.,Mutka, Tina S.,Luong, Lisa,Sargent, Justin,Kyle, Dennis E.,Manetsch, Roman
experimental part, p. 4399 - 4426 (2011/09/15)
Antimalarial activity of 1,2,3,4-tetrahydroacridin-9(10H)-ones (THAs) has been known since the 1940s and has garnered more attention with the development of the acridinedione floxacrine (1) in the 1970s and analogues thereof such as WR 243251 (2a) in the 1990s. These compounds failed just prior to clinical development because of suboptimal activity, poor solubility, and rapid induction of parasite resistance. Moreover, detailed structure-activity relationship (SAR) studies of the THA core scaffold were lacking and SPR studies were nonexistent. To improve upon initial findings, several series of 1,2,3,4-tetrahydroacridin-9(10H)-ones were synthesized and tested in a systematic fashion, examining each compound for antimalarial activity, solubility, and permeability. Furthermore, a select set of compounds was chosen for microsomal stability testing to identify physicochemical liabilities of the THA scaffold. Several potent compounds (EC50 100 nM) were identified to be active against the clinically relevant isolates W2 and TM90-C2B while possessing good physicochemical properties and little to no cross-resistance.
Potent antimalarial 4-pyridones with improved physico-chemical properties
Bueno, José M.,Manzano, Pilar,García, María C.,Chicharro, Jesús,Puente, Margarita,Lorenzo, Milagros,García, Adolfo,Ferrer, Santiago,Gómez, Rubén M.,Fraile, María T.,Lavandera, José L.,Fiandor, José M.,Vidal, Jaume,Herreros, Esperanza,Gargallo-Viola, Domingo
, p. 5214 - 5218 (2011/10/02)
Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous medi
Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials
Yeates, Clive L.,Batchelor, John F.,Capon, Edward C.,Cheesman, Neil J.,Fry, Mitch,Hudson, Alan T.,Pudney, Mary,Trimming, Helen,Woolven, James,Bueno, José M.,Chicharro, Jesús,Fernández, Esther,Fiandor, José M.,Gargallo-Viola, Domingo,De Las Heras, Federico Gómez,Herreros, Esperanza,León, María L.
, p. 2845 - 2852 (2008/12/23)
A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show > 500-fold improvement in IC50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc1 complex.
Novel heterocyclic compounds
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Page/Page column 28, (2008/06/13)
4-pyridone derivatives of Formula I and pharmaceutically acceptable derivatives thereof, processes for their preparation, pharmaceutical formulations thereof and their use in chemotherapy of certain parasitic infections such as malaria, are provided.
