Structure-activity relationships of Toxoplasma gondii cytochrome bc1 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.