Legacy 4(1 H)-Quinolone Scaffolds Activity against Acute and Chronic Toxoplasma gondii Infection
Toxoplasma gondii is a protozoan parasite capable of infecting most warm-blooded animals, including humans, and can cause severe disease in immunocompromised individuals and the developing fetus. Current treatments for toxoplasmosis are effective only against the acute stage of infection and have limited or no activity against the latent bradyzoite stage found within tissue cysts. The mitochondrion of T. gondii is a validated drug target, and the clinically used drug atovaquone acts by inhibiting the mitochondrial electron transport chain (ETC) at the coenzyme Q:cytochrome c oxidoreductase (bc1 complex). In this study, we evaluate two legacy 4(1H)-quinolones, ICI 56,780 and WR 243246, previously shown to inhibit the Plasmodium falciparum bc1 complex, for their efficacy against T. gondii. Both compounds inhibit tachyzoite growth with low-nanomolar EC50 values (0.34 nM for ICI 56,780 and 24 nM for WR 243246) and disrupt parasite mitochondrial function by blocking cytochrome c reduction and collapsing the mitochondrial membrane potential. Importantly, ICI 56,780 protects mice from lethal infection with type I RH tachyzoites. It also exhibits potent activity against chronic-stage parasites, reducing cyst size and bradyzoite viability in vitro and showing low-nanomolar EC50 values against in vivo-derived bradyzoites (EC50: 3.9 nM). In mice chronically infected with T. gondii, treatment with ICI 56,780 significantly decreases brain cyst burden. Although these 4(1H)-quinolones display some pharmacokinetic limitations, our findings highlight their potential as promising chemotypes active against both acute and chronic stages of T. gondii and provide a basis for future medicinal chemistry efforts to improve drug-like properties while preserving or enhancing antibradyzoite activity.
Melissa A Sleda, Khaly Diagne, Victoria Mills Clifton, Baihetiya Baierna, Roman Manetsch, Silvia N J Moreno. ACS Infect Dis. 2026 May 26. doi: 10.1021/acsinfecdis.5c01074.