Indole-Containing Pyrazino[2,1- b ]quinazoline-3,6-diones Active against Plasmodium 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- b ]quinazoline-3,6-diones containing indole alkaloids were explored for their antiparasitic potential against Plasmodium falciparum , Trypanosoma brucei , and Leishmania infantum . The synthetic libraries furnished promising hit compounds that are species specific ( 7, 12 ) or with broad antiparasitic activity ( 8 ). Structure-activity relationships were more evident for Plasmodium with anti-isomers (1 S ,4 R ) 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 in silico studies predicted these molecules as possible inhibitors for prolyl-tRNA synthetase both from Plasmodium and Leishmania . These results disclosed a potential new chemotype for further optimization toward novel and affordable antiparasitic drugs.