Monocyclic Nitro-heteroaryl Nitrones with Dual Mechanism of Activation: Synthesis and Antileishmanial Activity

Juliana Da Silva Pacheco, Débora De Souza Costa, Edézio Ferreira Cunha-Júnior, Valter Viana Andrade-Neto, Alan H. Fairlamb, Susan Wyllie, Marília O. F. Goulart, Danyelle C. Santos, Thaissa L. Silva, Marina A. Alves, Paulo R. R. Costa (Lead / Corresponding author), Ayres G. Dias (Lead / Corresponding author), Eduardo Caio Torres-Santos (Lead / Corresponding author)

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8 Citations (Scopus)
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5-Nitro-furan nitrones (1) and 5-nitro-thiophene nitrones (2) were synthesized in one step. Compounds 1a-c had the most potent leishmanicidal activity against intracellular amastigote forms of Leishmania amazonensis and L. infantum (from 0.019 to 2.76 μM), with excellent selectivity (from 39 to 5673). The comparison of the leishmanicidal activity in promastigotes of wild type L. donovani with those overexpressing nitroreductases NRT1 or NRT2 shows that 1a,b are activated by both, which could slow the development of resistance. Their redox potential (Eredox) obtained by cyclic voltammetry (-0.67 and -0.62 V) shows that the reduction of the nitro group is modulated by the nitrone group. Oral administration of 1b to mice infected by L. infantum reduced the parasite load on the spleen by 76.6 and 95.0% with doses of 50 and 100 mg/kg, respectively, administered twice a day, for 5 days. In the liver, the parasite load suppression was above 75% with either treatment.

Original languageEnglish
Pages (from-to)1405-1412
Number of pages8
JournalACS Medicinal Chemistry Letters
Issue number9
Early online date16 Aug 2021
Publication statusPublished - 9 Sept 2021


  • dual nitroreductase activation
  • leishmaniasis
  • Nitro-heteroaryl nitrones
  • NTR1/NTR2
  • redox potential

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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