AUTHOR=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. , Roberts Lucy , Hargrave Kerrie , Cong Hua , Sinai Anthony P. , Muench Stephen P. , Dubey Jitender P. , Prud'homme Robert K. , Lorenzi Hernan A. , Biagini Giancarlo A. , Moreno Silvia N. , Roberts Craig W. , Antonyuk Svetlana V. , Fishwick Colin W. G. , McLeod Rima 

TITLE=Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.00203

DOI=10.3389/fcimb.2020.00203

ISSN=2235-2988

ABSTRACT=<p>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 <italic>b</italic> inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces <italic>Toxoplasma gondii</italic> tachyzoites and encysted bradyzoites <italic>in vitro</italic>, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant <italic>Plasmodium falciparum in vitro</italic>. Causal prophylaxis and radical cure are achieved after <italic>P. berghei</italic> 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.</p>