Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites
Martin J. McPhillie, Ying Zhou, Mark Hickman, James A. Gordon, Christopher R. Weber, Qigui Li, Patty J. Lee, Kangsa Amporndanai, Rachel M. Johnson, Heather Darby, Stuart Woods, Zhu‐Hong Li, Richard Priestley, Kurt D. Ristroph, Scott B. Biering, Kamal El Bissati, Seungmin Hwang, Farida E. Hakim, Sarah Dovgin, Joseph Lykins, Lucy Roberts, Kerrie E Hargrave, Hua Cong, Anthony P. Sinai, Stephen P. Muench, J. P. Dubey, Robert K. Prud’homme, Hernán Lorenzi, Giancarlo A. Biagini, Silvia N.J. Moreno, Craig W. Roberts, S.V. Antonyuk, Colin W. G. Fishwick, Rima McLeod
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 cytochromeb 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 infections in vivo. 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 (2.5mg/kg) or three days treatment at reduced dose (0.625mg/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.