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

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

  • ACS Med Chem Lett. 2022 Jan 11;13(2):225-235. doi: 10.1021/acsmedchemlett.1c00589.
Solida Long 1 2,  Denise Duarte 3,  Carla Carvalho 4,  Rafael Oliveira 3,  Nuno Santarém 4,  Andreia Palmeira 1 5,  Diana I S P Resende 1 5,  Artur M S Silva 6,  Rui Moreira 7,  Anake Kijjoa 5 8,  Anabela Cordeiro da Silva 4 9,  Fátima Nogueira 3,  Emília Sousa 1 5,  Madalena M M Pinto 1 5
Affiliations

Affiliations

  • 1 Laboratório de Química Orgânica e Farmacêutica, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal.
  • 2 Department of Bioengineering, Royal University of Phnom Penh, Russian Confederation Blvd, 12156 Phnom Penh, Cambodia.
  • 3 Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, 1349-008 Lisboa, Portugal.
  • 4 Parasite Disease Group, IBMC-Instituto de Biologia Molecular e Celular, Rua Alfredo Allen, 4200-135 Porto, Portugal.
  • 5 CIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal.
  • 6 QOPNA - Química Orgânica, Produtos Naturais e Agroalimentares, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
  • 7 Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia, Universidade de Lisboa, 1649-019 Lisboa, Portugal.
  • 8 ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal.
  • 9 Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal.
PMID: 35178179 DOI: 10.1021/acsmedchemlett.1c00589
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.

Figures