Sci Rep. 2016 Jul 14;6:29179. doi: 10.1038/srep29179.
McPhillie M1,
Zhou Y2,
El Bissati K2,
Dubey J3,
Lorenzi H4,
Capper M5,
Lukens AK6,7,
Hickman M8,
Muench S1,
Verma SK3,
Weber CR2,
Wheeler K2,
Gordon J1,
Sanders J9,
Moulton H9,
Wang K10,
Kim TK10,
He Y10,
Santos T11,
Woods S12,
Lee P8,
Donkin D8,
Kim E8,
Fraczek L2,
Lykins J2,
Esaa F2,
Alibana-Clouser F2,
Dovgin S2,
Weiss L11,
Brasseur G13,
Wirth D6,7,
Kent M9,
Hood L10,
Meunieur B14,
Roberts CW12,
Hasnain SS5,
Antonyuk SV5,
Fishwick C1,
McLeod R2.
Abstract
Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc1 complex Qi site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 30 nM) and cysts (IC50, 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC50, <30 abstracttext="" and="" bc1="" billion="" binding="" bradyzoites.="" chronically="" clinically="" co-crystallographic="" complex="" demonstrate="" direct="" encysted="" for="" have="" impact="" improving="" infected="" malaria="" mutant="" nbsp="" nm="" on="" our="" outcomes="" persons="" qi="" relevant="" results="" site.="" studies="" synergy.="" the="" those="" to="" toxoplasmosis="" with="" yeast="">30>
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