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

Solida Long, Denise Duarte, Carla Carvalho, Rafael Oliveira, Nuno Santarém, Andreia Palmeira, Diana I. S. P. Resende, Artur M. S. Silva, Rui Moreira, Anake Kijjoa, Anabela Cordeiro Da Silva, Fátima Nogueira, Emília Sousa, Madalena M. M. Pinto

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Abstract

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 (1S,4R) 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.

Original languageEnglish
Pages (from-to)225-235
Number of pages11
JournalACS Medicinal Chemistry Letters
Volume13
Issue number2
Early online date11 Jan 2022
DOIs
Publication statusPublished - 10 Feb 2022

Keywords

  • Pyrazino[2,1- b]quinazoline-3,6-dione
  • antimalarial
  • P. falciparum
  • Leishmania
  • Trypanosoma brucei

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