2. Academic Validation
  3. N, N', N″-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity

N, N', N″-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity

  • Eur J Med Chem. 2019 Jun 1:171:116-128. doi: 10.1016/j.ejmech.2019.03.032.
Rafael Dias do Espírito Santo 1,  Ángela María Arenas Velásquez 2,  Luana Vitorino Gushiken Passianoto 1,  Alex Arbey Lopera Sepulveda 2,  Leandro da Costa Clementino 2,  Renata Pires Assis 2,  Amanda Martins Baviera 2,  Predrag Kalaba 3,  Fábio Neves Dos Santos 4,  Marcos Nogueira Éberlin 4,  Gil Valdo José da Silva 5,  Martin Zehl 6,  Gert Lubec 7,  Márcia Aparecida Silva Graminha 8,  Eduardo René Pérez González 9
Affiliations

Affiliations

  • 1 Laboratório de Química Orgânica Fina, Departamento de Química e Biologia, Faculdade de Ciências e Tecnologia, Universidade Estadual Paulista - UNESP, Campus de Presidente Prudente, Rua Roberto Simonsen, 305, 19060-900, Presidente Prudente, SP, Brazil; Programa de Pós-Graduação em Ciência e Tecnologia de Materiais (POSMAT), Universidade Estadual Paulista - UNESP, São Paulo, Brazil.
  • 2 Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista - UNESP, Campus de Araraquara, Rodovia Araraquara-Jaú, km1, 14800-903, Araraquara, SP, Brazil.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
  • 4 Laboratório ThoMSon de Espectrometria de Massas, Instituto de Química, Universidade de Campinas - UNICAMP, Campinas, 13083-970, SP, Brazil.
  • 5 Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo - USP, Avenida dos Bandeirantes, 3900, 14040-901, Ribeirão Preto, SP, Brazil.
  • 6 Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
  • 7 Department of Neuroproteomics, Paracelsus Medical University, Salzburg, Austria.
  • 8 Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista - UNESP, Campus de Araraquara, Rodovia Araraquara-Jaú, km1, 14800-903, Araraquara, SP, Brazil. Electronic address: marcia.graminha@unesp.br.
  • 9 Laboratório de Química Orgânica Fina, Departamento de Química e Biologia, Faculdade de Ciências e Tecnologia, Universidade Estadual Paulista - UNESP, Campus de Presidente Prudente, Rua Roberto Simonsen, 305, 19060-900, Presidente Prudente, SP, Brazil; Programa de Pós-Graduação em Ciência e Tecnologia de Materiais (POSMAT), Universidade Estadual Paulista - UNESP, São Paulo, Brazil. Electronic address: eduardo.gonzalez@unesp.br.
PMID: 30913526 DOI: 10.1016/j.ejmech.2019.03.032
Abstract

Leishmaniasis is a group of diseases caused by protozoan parasites from the genus Leishmania. There are estimated 1.3 million new cases annually with a mortality of 20,000-30,000 per year, when patients are left untreated. Current chemotherapeutic drugs available present high toxicity and low efficacy, the latter mainly due to the emergence of drug-resistant parasites, which makes discovery of novel, safe, and efficacious antileishmanial drugs mandatory. The present work reports the synthesis, characterization by ESI-MS, 1H and 13C NMR, and FTIR techniques as well as in vitro and in vivo evaluation of leishmanicidal activity of guanidines derivatives presenting lower toxicity. Among ten investigated compounds, all being guanidines containing a benzoyl, a benzyl, and a substituted phenyl moiety, LQOF-G2 (IC50-ama 5.6 μM; SI = 131.8) and LQOF-G7 (IC50-ama 7.1 μM; SI = 87.1) were the most active against L. amazonensis intracellular amastigote, showing low cytotoxicity to the host cells according to their selectivity index. The most promising compound, LQOF-G2, was further evaluated in an in vivo model and was able to decrease 60% of the Parasite load in foot lesions at a dose of 0.25 mg/kg/day. Moreover, this guanidine derivative demonstrated reduced hepatotoxicity compared to Other leishmanicidal compounds and did not show nephrotoxicity, as determined by the analyses of biomarkers of hepatic damage and renal function, which make this compound a potential new hit for therapy against leishmaniasis.

Keywords

Hepatoprotective effect; In vivo leishmanicidal activity; Leishmania amazonensis; Leishmaniasis; N, N′, N″-trisubstituted guanidine derivatives.

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