Discovery of new potent hits against intracellular Trypanosoma cruzi by QSAR-based virtual screening.

Abstract

Chagas disease is a neglected tropical disease (NTD) caused by the protozoan parasite Trypanosoma cruzi and is primarily transmitted to humans by the feces of infected Triatominae insects during their blood meal. The disease affects 6-8 million people, mostly in Latin America countries, and kills more people in the region each year than any other parasite-born disease, including malaria. Moreover, patient numbers are currently increasing in non-endemic, developed countries, such as Australia, Japan, Canada, and the United States. The treatment is limited to one drug, benznidazole, which is only effective in the acute phase of the disease and is very toxic. Thus, there is an urgent need to develop new, safer, and effective drugs against the chronic phase of Chagas disease. Using a QSAR-based virtual screening followed by in\xa0vitro experimental evaluation, we report herein the identification of novel potent and selective hits against T.\xa0cruzi intracellular stage. We developed and validated binary QSAR models for prediction of anti-trypanosomal activity and cytotoxicity against mammalian cells using the best practices for QSAR modeling. These models were then used for virtual screening of a commercial database, leading to the identification of 39 virtual hits. Further in\xa0vitro assays showed that seven compounds were potent against intracellular T.\xa0cruzi at submicromolar concentrations (EC50\u202f<\u202f1\u202fμM) and were very selective (SI\u202f>\u202f30). Furthermore, other six compounds were also inside the hit criteria for Chagas disease, which presented activity at low micromolar concentrations (EC50\u202f<\u202f10\u202fμM) against intracellular T.\xa0cruzi and were also selective (SI\u202f>\u202f15). Moreover, we performed a multi-parameter analysis for the comparison of tested compounds regarding their balance between potency, selectivity, and predicted ADMET properties. In the next studies, the most promising compounds will be submitted to additional in\xa0vitro and in\xa0vivo assays in acute model of Chagas disease, and can be further optimized for the development of new promising drug candidates against this important yet neglected disease.