Potent tetrahydroquinolone eliminates apicomplexan parasites

McPhillie, Martin J and Zhou, Ying and Hickman, Mark R and Gordon, James A. and Weber, Christopher R. and Li, Qigui and Lee, Patty J. and Amporndanai, Kangsa and Johnson, Rachel M. and Darby, Heather and Woods, Stuart and Li, Zhu-hong and Priestley, Richard S. and Ristroph, Kurt D. and Biering, Scott B. and El Bissati, Kamal and Hwang, Seungmin and Hakim, Farida Esaa and Dovgin, Sarah M. and Lykins, Joseph D. and Roberts, Lucy and Hargrave, Kerrie and Cong, Hua and Sinai, Anthony P. and Muench, Stephen P. and Dubey, Jitender P. and Prud'homme, Robert K. and Lorenzi, Hernan A. and Biagini, Giancarlo A. and Moreno, Silvia N. and Roberts, Craig W. and Antonyuk, Svetlana V. and Fishwick, Colin W. G. and McLeod, Rima (2020) Potent tetrahydroquinolone eliminates apicomplexan parasites. Frontiers in Cellular and Infection Microbiology : Parasite and Host, 10. 203. ISSN 2235-2988

[thumbnail of McPhilllie-etal-FICIM-2020-Potent-tetrahydroquinolone-eliminates-apicomplexan]
Text (McPhilllie-etal-FICIM-2020-Potent-tetrahydroquinolone-eliminates-apicomplexan)
Final Published Version
License: Creative Commons Attribution 4.0 logo

Download (6MB)| Preview


    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

    ORCID iDs

    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 ORCID logoORCID: https://orcid.org/0000-0002-3798-2074, 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 ORCID logoORCID: https://orcid.org/0000-0001-6015-4616, 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. ORCID logoORCID: https://orcid.org/0000-0002-0653-835X, Antonyuk, Svetlana V., Fishwick, Colin W. G. and McLeod, Rima;