Trypanocidal properties, structure-activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives

Yannick Estevez, Miguel Quiliano, Asunción Burguete, Billy Cabanillas, Mirko Zimic, Edith Málaga, Manuela Verástegui, Silvia Pérez-Silanes, Ignacio Aldana, Antonio Monge, Denis Castillo, Eric Deharo

Research output: Contribution to journalArticlepeer-review

Abstract

Pyrazole and propenone quinoxaline derivatives were tested against intracellular forms of Leishmania peruviana and Trypanosoma cruzi. Both series were tested for toxicity against proliferative and non-proliferative cells. The pyrazole quinoxaline series was quite inactive against T. cruzi; however, the compound 2,6-dimethyl-3-f-quinoxaline 1,4-dioxide was found to inhibit 50% of Leishmania growth at 8.9. μM, with no impact against proliferative kidney cells and with low toxicity against THP-1 cells and murine macrophages. The compounds belonging to the propenone quinoxaline series were moderately active against T. cruzi. Among these compounds, two were particularly interesting, (2E)-1-(7-fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone and (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone. The former possessed selective activity against proliferative cells (cancer and parasites) and was inactive against murine peritoneal macrophages; the latter was active against Leishmania and inactive against the other tested cells. Furthermore, in silico studies showed that both series respected Lipinski's rules and that they confirmed a linear correlation between trypanocidal activities and Log. P. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.

Original languageEnglish (US)
Pages (from-to)745-751
Number of pages7
JournalExperimental Parasitology
Volume127
Issue number4
DOIs
StatePublished - Apr 2011

Keywords

  • Leishmania peruviana
  • Quinoxaline 1,4-di-N-oxide derivatives
  • Trypanosoma cruzi

ASJC Scopus subject areas

  • Parasitology
  • Immunology
  • Infectious Diseases

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