Improvements in potency and selectivity of triazine nitrile inhibitors targeting Toxoplasma gondii cathepsin L for the treatment of latent toxoplasmosis.

The protozoan Toxoplasma gondii is one of the most prevalent infectious agents, having infected approximately one third of the global population. It remains a leading cause of deaths due to foodborne illness, can cause serious complications in immunocompromised and pregnant women, and is associated with vision loss and mental illnesses including schizophrenia and major depressive disorder. Current treatments target symptoms associated with the acute, fast-replicating form of the parasite, but fail to clear the body of the chronic, slow-replicating form of the parasite that persists in tissues, including the central nervous system (CNS). In this study, we report efforts to improve the selectivity of previously reported triazine nitrile inhibitors of T. gondii cathepsin protease L over human cathepsin L. With the help of computational modeling, different structural design approaches were used to improve inhibitor potency and selectivity including conformationally restricted scaffold modifications, basic and polar groups, and nonaromatic groups. From these approaches, we maintained strong inhibitor potency (<100 nM IC50 values) and identified key features in the triazine nitrile inhibitors that helped improve selectivity (up to 30-fold versus human cathepsin L) and physicochemical properties.