873203-36-2Relevant academic research and scientific papers
Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites
Amporndanai, Kangsa,Antonyuk, Svetlana V.,Biagini, Giancarlo A.,Biering, Scott B.,Cong, Hua,Darby, Heather,Dovgin, Sarah M.,Dubey, Jitender P.,El Bissati, Kamal,Fishwick, Colin W. G.,Gordon, James A.,Hakim, Farida Esaa,Hargrave, Kerrie,Hickman, Mark R.,Hwang, Seungmin,Johnson, Rachel M.,Lee, Patty J.,Li, Qigui,Li, Zhu-Hong,Lorenzi, Hernan A.,Lykins, Joseph D.,McLeod, Rima,McPhillie, Martin J.,Moreno, Silvia N.,Muench, Stephen P.,Priestley, Richard S.,Prud'homme, Robert K.,Ristroph, Kurt D.,Roberts, Craig W.,Roberts, Lucy,Sinai, Anthony P.,Weber, Christopher R.,Woods, Stuart,Zhou, Ying
, (2020)
Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.
New Scalable Synthetic Routes to ELQ-300, ELQ-316, and Other Antiparasitic Quinolones
Pou, Sovitj,Dodean, Rozalia A.,Frueh, Lisa,Liebman, Katherine M.,Gallagher, Rory T.,Jin, Haihong,Jacobs, Robert T.,Nilsen, Aaron,Stuart, David R.,Doggett, J. Stone,Riscoe, Michael K.,Winter, Rolf W.
supporting information, p. 1841 - 1852 (2021/08/24)
The endochin-like quinolone (ELQ) compound class may yield effective, safe treatments for a range of important human and animal afflictions. However, to access the public health potential of this compound series, a synthetic route needed to be devised, which would lower costs and be amenable to large-scale production. In the new synthetic route described here, a substituted β-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad-Limpach reaction to produce 3-substituted 4(1H)-quinolones such as ELQ-300 and ELQ-316. This synthetic route, the first described to be truly amenable to industrial-scale production, is relatively short (five reaction steps), does not require palladium, chromatographic separation, or protecting group chemistry, and may be performed without high vacuum distillation.
COMPOUNDS AND METHODS FOR TREATING, DETECTING, AND IDENTIFYING COMPOUNDS TO TREAT APICOMPLEXAN PARASITIC DISEASES
-
Page/Page column 107, (2017/07/14)
Disclosed herein; are novel compounds for treating apicomplexan parasite related disorders, methods for their use; cell line and non-human animal models of the dormant parasite phenotype and methods for their use in identifying new drugs to teat apicomplexan parasite related disorders, and biomarkers to identify disease due to the parasite and its response to treatment.
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.
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
scheme or table, 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
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.
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
-
Page/Page column 27, (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.
