Parasitic diseases continue to pose serious health threat globally and thus exert substantial burden on healthcare systems and worker’s productivity. Toxoplasmosis (caused by Toxoplasma gondii) and cryptosporidiosis (caused by Cryptosporidium parvum) are prevalent parasitic diseases especially dangerous to young children and immunocompromised individuals. Additionally, T. gondii can enter the persistent stage of the infection by creating pseudocysts usually in muscle and brain tissues, which might have a profound impact on development of congenitally infected neonates. C. parvum is also considered to be an important veterinary pathogen responsible for a diarrheal syndrome in neonatal bovine calves, thus resulting in substantial economic losses for farmers. The current pharmacological treatment options for infections caused by those parasites are largely limited due to severe adverse effects of the approved medications. In addition, there is no approved agent that would be effective against the cyst stage of T. gondii. Accordingly, there is an increasing need for discovery and development of safe and effective small molecule-based therapeutics for the treatment of toxoplasmosis and cryptosporidiosis. Herein, we present an efficient synthesis and biological evaluation of a diverse set of small molecules that show inhibitory activity against the growth of T. gondii and C. parvum. Among the tested compounds, several showed low micromolar activity against both parasites, while a few derivatives showed selective growth inhibition of either T. gondii or C. parvum (Figure 1). Importantly, two compounds decreased the number of Toxoplasma cysts in the brains of infected Brown Norway rats. Together, these preliminary results provide a viable starting point for medicinal chemistry structure optimization in search of novel agents with prospective use as treatments for toxoplasmosis and cryptosporidiosis.

In search of novel agents active against Toxoplasma gondii and Cryptosporidium parvum

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ACS Fall 2022

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