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Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites

Authors :
Martin J. McPhillie
Ying Zhou
Mark R. 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 S. Priestley
Kurt D. Ristroph
Scott B. Biering
Kamal El Bissati
Seungmin Hwang
Farida Esaa Hakim
Sarah M. Dovgin
Joseph D. Lykins
Lucy Roberts
Kerrie Hargrave
Hua Cong
Anthony P. Sinai
Stephen P. Muench
Jitender P. Dubey
Robert K. Prud'homme
Hernan A. Lorenzi
Giancarlo A. Biagini
Silvia N. Moreno
Craig W. Roberts
Svetlana V. Antonyuk
Colin W. G. Fishwick
Rima McLeod
Source :
Frontiers in Cellular and Infection Microbiology, Vol 10 (2020)
Publication Year :
2020
Publisher :
Frontiers Media S.A., 2020.

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.

Details

Language :
English
ISSN :
22352988
Volume :
10
Database :
Directory of Open Access Journals
Journal :
Frontiers in Cellular and Infection Microbiology
Publication Type :
Academic Journal
Accession number :
edsdoj.2c4f99fc24ed49b8a965b629b176459d
Document Type :
article
Full Text :
https://doi.org/10.3389/fcimb.2020.00203