Biological activity of 1,2,3-triazole-2-amino-1,4-naphthoquinone derivatives and their evaluation as therapeutic strategy for malaria control

  • Eur J Med Chem. 2023 Jul 5;255:115400. doi: 10.1016/j.ejmech.2023.115400.
Renata Maria Costa Souza  1 ,  Lilian Maria Lapa Montenegro Pimentel  2 ,  Laryssa Kathleen Mendonça Ferreira  3 ,  Valéria Rêgo Alves Pereira  4 ,  Aline Caroline Da Silva Santos  4 ,  Willyenne Marília Dantas  5 ,  Carla Jasmine Oliveira Silva  6 ,  Ramayana Morais De Medeiros Brito  7 ,  José Lucas Andrade  8 ,  Valter Ferreira De Andrade-Neto  8 ,  Ricardo Toshio Fujiwara  9 ,  Lilian Lacerda Bueno  9 ,  Valdemiro Amaro Silva Junior  10 ,  Lindomar Pena  11 ,  Celso Amorim Camara  6 ,  Brijesh Rathi  12 ,  Ronaldo Nascimento De Oliveira  13
Affiliations
  • 1. Department of Immunology, Laboratory of Immunoepidemiology of Aggeu Magalhães Institute, Fiocruz-PE, Recife, Pernambuco, Brazil; Department of Chemistry, Laboratory of Synthesis of Bioactive Compounds, Federal Rural University of Pernambuco, Recife, Pernambuco, Brazil.
  • 2. Department of Immunology, Laboratory of Immunoepidemiology of Aggeu Magalhães Institute, Fiocruz-PE, Recife, Pernambuco, Brazil. Electronic address: [email protected].
  • 3. Department of Immunology, Laboratory of Immunoepidemiology of Aggeu Magalhães Institute, Fiocruz-PE, Recife, Pernambuco, Brazil.
  • 4. Department of Immunology, Laboratory of Immunoparasitology, Aggeu Magalhães Institute, Fiocruz-PE, Recife, Pernambuco, Brazil.
  • 5. Department of Virology and Experimental Therapy Aggeu Magalhães Institute - Fiocruz-PE, Recife, Pernambuco, Brazil; Department of Chemistry, Laboratory of Synthesis of Bioactive Compounds, Federal Rural University of Pernambuco, Recife, Pernambuco, Brazil.
  • 6. Department of Chemistry, Laboratory of Synthesis of Bioactive Compounds, Federal Rural University of Pernambuco, Recife, Pernambuco, Brazil.
  • 7. Department of Microbiology and Parasitology, Laboratory of Malaria and Toxoplasmosis Biology, LaBMAT/DMP/CB, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil; Department of Parasitology, Laboratory of Immunobiology and Parasites Control, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
  • 8. Department of Microbiology and Parasitology, Laboratory of Malaria and Toxoplasmosis Biology, LaBMAT/DMP/CB, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil.
  • 9. Department of Parasitology, Laboratory of Immunobiology and Parasites Control, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
  • 10. Department of Veterinary Medicine, Federal Rural University of Pernambuco, Recife, Pernambuco, Brazil.
  • 11. Department of Virology and Experimental Therapy Aggeu Magalhães Institute - Fiocruz-PE, Recife, Pernambuco, Brazil.
  • 12. Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi, 110007, India.
  • 13. Department of Chemistry, Laboratory of Synthesis of Bioactive Compounds, Federal Rural University of Pernambuco, Recife, Pernambuco, Brazil. Electronic address: [email protected].
PMID: 37130472 DOI: 10.1016/j.ejmech.2023.115400
Abstract

Malaria can be caused by several Plasmodium species and the development of an effective vaccine is challenging. Currently, the most effective tool to control the disease is the administration of specific chemotherapy; however, resistance to the frontline antimalarials is one of the major problems in malaria control and thus the development of new drugs becomes urgent. The study presented here sought to evaluate the antimalarial activities of compounds derived from 2-amino-1,4-naphthoquinones containing 1,2,3-triazole using in vivo and in vitro models. 1H-1,2,3-Triazole 2-amino-1,4-naphthoquinone derivatives were synthesized and evaluated for antimalarial activity in vitro, using P. falciparum W2 chloroquine (CQ) resistant strain and in vivo using the murine-P. berghei ANKA strain. Acute toxicity was determined as established by the OECD (2001). Cytotoxicity was evaluated against HepG2 and Vero mammalian cell lines. Transmission electron microscopy of the Plasmodium falciparum trophozoite (early and late stages) was used to evaluate the action of compounds derived at ultra-structural level. The compounds displayed low cytotoxicity CC50 > 100 μM, neither did they cause hemolysis at the tested doses and nor the signs of toxicity in the in vivo acute toxicity test. Among the five compounds tested, one showed IC50 values in submicromolar range of 0.8 μM. Compounds 7, 8 and 11 showed IC50 values < 5 μM, and selectivity index (SI) ranging from 6.8 to 343 for HepG2, and from 13.7 to 494.8 for Vero cells. Compounds 8 and 11 were partially active against P. berghei induced parasitemia in vivo. Analysis of the ultrastructural changes associated with the treatment of these two compounds, showed trophozoites with completely degraded cytoplasm, loss of membrane integrity, organelles in the decomposition stage and possible food vacuole deterioration. Our results indicated that compounds 8 and 11 may be considered hit molecules for antimalarial drug discovery platform and deserve further optimization studies.

Keywords
1,2,3-Triazole; Amino-naphthoquinone; Antimalarials; Malaria; Plasmodium.
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