2. Academic Validation
  3. Monocyclic Nitro-heteroaryl Nitrones with Dual Mechanism of Activation: Synthesis and Antileishmanial Activity

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

  • ACS Med Chem Lett. 2021 Aug 16;12(9):1405-1412. doi: 10.1021/acsmedchemlett.1c00193.
Juliana da Silva Pacheco 1,  Débora de Souza Costa 2,  Edézio Ferreira Cunha-Júnior 1,  Valter Viana Andrade-Neto 1,  Alan H Fairlamb 3,  Susan Wyllie 3,  Marília O F Goulart 4,  Danyelle C Santos 4,  Thaissa L Silva 5,  Marina A Alves 6,  Paulo R R Costa 2,  Ayres G Dias 7,  Eduardo Caio Torres-Santos 1
Affiliations

Affiliations

  • 1 FIOCRUZ, Instituto Oswaldo Cruz, Laboratório de Bioquímica de Tripanosomatídeos, Rio de Janeiro, RJ, Brazil.
  • 2 Universidade Federal do Rio de Janeiro, Instituto de Pesquisas de Produtos Naturais, Laboratório de Química Bioorgânica, Rio de Janeiro, RJ, Brazil.
  • 3 University of Dundee, School of Life Sciences, Division of Biological Chemistry and Drug Discovery, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.
  • 4 Universidade Federal de Alagoas, Instituto de Química e Biotecnologia, Maceió, AL, Brazil.
  • 5 Universidade Federal de Alagoas, Núcleo de Ciências Exatas, Campus de Arapiraca, Arapiraca, AL, Brazil.
  • 6 Universidade Federal do Rio de Janeiro, Laboratório de Apoio ao Desenvolvimento Tecnológico, Rio de Janeiro, RJ, Brazil.
  • 7 Universidade do Estado do Rio de Janeiro, Centro de Tecnologia e Ciências, Departamento de Química Orgânica, Rio de Janeiro, RJ, Brazil.
PMID: 34531949 DOI: 10.1021/acsmedchemlett.1c00193
Abstract

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 (E redox) 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.

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