Structure-activity relationships of Toxoplasma gondii cytochrome bc₁ inhibitors

Toxoplasma gondii is a prolific apicomplexan parasite that infects human and nonhuman animals worldwide and can cause severe brain and eye disease. Safer, more effective therapies for toxoplasmosis are needed. Cytochrome bc₁ inhibitors are remarkably effective against toxoplasmosis and other apicomplexan-caused diseases.

This work reviews T. gondii cytochrome bc₁ inhibitors. Emphasis is placed on the structure-activity relationships of these inhibitors with regard to efficacy, pharmacokinetics, selectivity of T. gondii cytochrome bc₁ over host, safety, and potential therapeutic strategies.

Cytochrome bc₁ inhibitors are highly promising compounds for toxoplasmosis that have been effective in clinical and preclinical studies. Clinical experience with atovaquone previously validated cytochrome bc₁ as a tractable drug target and, over the past decade, optimization of cytochrome bc₁ inhibitors has resulted in improved bioavailability, metabolic stability, potency, blood-brain barrier penetration, and selectivity for the T. gondii cytochrome bc₁ over the mammalian bc₁. Recent studies have demonstrated preclinical safety, identified novel therapeutic strategies for toxoplasmosis using synergistic combinations or long-acting administration and provided insight into their role in chronic infection. This research has identified drug candidates that are more effective than clinically used drugs in preclinical measures of efficacy.