Indole-Containing Pyrazino[2,1-]quinazoline-3,6-diones Active against and Trypanosomatids.

Malaria, leishmaniasis, and sleeping sickness are potentially fatal diseases that represent a real health risk for more than 3,5 billion people. New antiparasitic compounds are urgent leading to a constant search for novel scaffolds. Herein, pyrazino[2,1-]quinazoline-3,6-diones containing indole alkaloids were explored for their antiparasitic potential against , , and . The synthetic libraries furnished promising hit compounds that are species specific () or with broad antiparasitic activity (). Structure-activity relationships were more evident for with anti-isomers (1,4) possessing excellent antimalarial activity, while the presence of a substituent on the anthranilic acid moiety had a negative effect on the activity. Hit compounds against malaria did not inhibit β-hematin, and studies predicted these molecules as possible inhibitors for prolyl-tRNA synthetase both from and . These results disclosed a potential new chemotype for further optimization toward novel and affordable antiparasitic drugs.