1. Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites.
- Author
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McPhillie, Martin J., Zhou, Ying, Hickman, Mark R., Gordon, James A., Weber, Christopher R., Li, Qigui, Lee, Patty J., Amporndanai, Kangsa, Johnson, Rachel M., Darby, Heather, Woods, Stuart, Li, Zhu-hong, Priestley, Richard S., Ristroph, Kurt D., Biering, Scott B., El Bissati, Kamal, Hwang, Seungmin, Hakim, Farida Esaa, Dovgin, Sarah M., and Lykins, Joseph D.
- Subjects
CYTOCHROME b ,TOXOPLASMA gondii ,PARASITES ,PLASMODIUM falciparum ,LEAD compounds ,TOXOPLASMOSIS - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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