873203-36-2Relevant articles and documents
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.
COMPOUNDS AND METHODS FOR TREATING, DETECTING, AND IDENTIFYING COMPOUNDS TO TREAT APICOMPLEXAN PARASITIC DISEASES
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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.
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
