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- Title
Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites.
- Authors
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.; Lykins, Joseph D.
- 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.
- Subjects
CYTOCHROME b; TOXOPLASMA gondii; PARASITES; PLASMODIUM falciparum; LEAD compounds; TOXOPLASMOSIS
- Publication
Frontiers in Cellular & Infection Microbiology, 2020, Vol 10, p1
- ISSN
2235-2988
- Publication type
Article
- DOI
10.3389/fcimb.2020.00203