Structure-activity relationships of Toxoplasma gondii cytochrome bc ₁ inhibitors

Introduction: 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 bc ₁ inhibitors are remarkably effective against toxoplasmosis and other apicomplexan-caused diseases. Areas covered: This work reviews T. gondii cytochrome bc ₁ inhibitors. Emphasis is placed on the structure–activity relationships of these inhibitors with regard to efficacy, pharmacokinetics, selectivity of T. gondii cytochrome bc ₁ over host, safety, and potential therapeutic strategies. Expert opinion: Cytochrome bc ₁ inhibitors are highly promising compounds for toxoplasmosis that have been effective in clinical and preclinical studies. Clinical experience with atovaquone previously validated cytochrome bc ₁ as a tractable drug target and, over the past decade, optimization of cytochrome bc ₁ inhibitors has resulted in improved bioavailability, metabolic stability, potency, blood–brain barrier penetration, and selectivity for the T. gondii cytochrome bc ₁ over the mammalian bc ₁. 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.