2. Academic Validation
  3. Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity

Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity

  • Eur J Med Chem. 2014 Jul 23:82:418-25. doi: 10.1016/j.ejmech.2014.05.077.
Ricardo Augusto Massarico Serafim 1,  José Eduardo Gonçalves 2,  Felipe Pereira de Souza 3,  Ana Paula de Melo Loureiro 3,  Silvia Storpirtis 2,  Renata Krogh 4,  Adriano Defini Andricopulo 4,  Luiz Carlos Dias 5,  Elizabeth Igne Ferreira 6
Affiliations

Affiliations

  • 1 LAPEN - Laboratório de Planejamento e Síntese de Quimioterápicos Potencialmente Ativos contra Doenças Negligenciadas, Universidade de São Paulo (USP), Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, Av. Prof. Lineu Prestes, 580, 05508-900 São Paulo, SP, Brazil.
  • 2 LPFCC - Laboratório de Permeabilidade de Fármacos em Culturas Celulares, Universidade de São Paulo (USP), Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, São Paulo, SP, Brazil.
  • 3 Universidade de São Paulo, Departamento de Análises Clínicas e Toxicológicas, São Paulo, SP, Brazil.
  • 4 LQMC - Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Universidade de São Paulo (USP), Instituto de Física de São Carlos, São Carlos, SP, Brazil.
  • 5 LQOS - Laboratório de Química Orgânica Sintética, Universidade Estadual de Campinas (UNICAMP), Instituto de Química, Campinas, SP, Brazil.
  • 6 LAPEN - Laboratório de Planejamento e Síntese de Quimioterápicos Potencialmente Ativos contra Doenças Negligenciadas, Universidade de São Paulo (USP), Faculdade de Ciências Farmacêuticas, Departamento de Farmácia, Av. Prof. Lineu Prestes, 580, 05508-900 São Paulo, SP, Brazil. Electronic address: elizabeth.igne@gmail.com.
PMID: 24929292 DOI: 10.1016/j.ejmech.2014.05.077
Abstract

Hybrid bioisoster derivatives from N-acylhydrazones and furoxan groups were designed with the objective of obtaining at least a dual mechanism of action: cruzain inhibition and nitric oxide (NO) releasing activity. Fifteen designed compounds were synthesized varying the substitution in N-acylhydrazone and in furoxan group as well. They had its anti-Trypanosoma cruzi activity in amastigotes forms, NO releasing potential and inhibitory cruzain activity evaluated. The two most active compounds (6, 14) both in the Parasite amastigotes and in the Enzyme contain the nitro group in para position of the aromatic ring. The permeability screening in Caco-2 cell and cytotoxicity assay in human cells were performed for those most active compounds and both showed to be less cytotoxic than the reference drug, benznidazole. Compound 6 was the most promising, since besides activity it showed good permeability and selectivity index, higher than the reference drug. Thereby the compound 6 was considered as a possible candidate for additional studies.

Keywords

Anti-Trypanosoma cruzi compounds; Bioisosters; Furoxan derivatives; Molecular hybrids; N-acylhydrazone derivatives; Nitric oxide donor groups.

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