2. Academic Validation
  3. Design, synthesis and antitrypanosomatid activity of 2-nitroimidazole-3,5-disubstituted isoxazole compounds based on benznidazole

Design, synthesis and antitrypanosomatid activity of 2-nitroimidazole-3,5-disubstituted isoxazole compounds based on benznidazole

  • Eur J Med Chem. 2023 Nov 15:260:115451. doi: 10.1016/j.ejmech.2023.115451.
Diego B Carvalho 1,  Pedro A N Costa 2,  Gisele B Portapilla 3,  Amarith R das Neves 2,  Cristiane Y K Shiguemoto 1,  Bruno I Pelizaro 1,  Fernanda Silva 4,  Eliane M Piranda 4,  Carla C P Arruda 4,  Priscyla D M Gaspari 5,  Iara A Cardoso 6,  Pedro H Luccas 6,  M Cristina Nonato 6,  Norberto P Lopes 7,  Sergio de Albuquerque 3,  Adriano C M Baroni 8
Affiliations

Affiliations

  • 1 Laboratório de Síntese e Química Medicinal (LASQUIM), Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grossso do Sul- UFMS, Campo Grande, Mato Grosso do Sul, CEP 79051-470, Brazil.
  • 2 Laboratório de Síntese e Química Medicinal (LASQUIM), Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grossso do Sul- UFMS, Campo Grande, Mato Grosso do Sul, CEP 79051-470, Brazil; Laboratório de Parasitologia Humana, Instituto de Biociências, Universidade Federal de Mato Grossso do Sul- UFMS, Campo Grande, Mato Grosso do Sul, CEP 79070-900, Brazil.
  • 3 Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - Universidade de São Paulo, Ribeirão Preto, São Paulo, CEP 14040-900, Brazil.
  • 4 Laboratório de Parasitologia Humana, Instituto de Biociências, Universidade Federal de Mato Grossso do Sul- UFMS, Campo Grande, Mato Grosso do Sul, CEP 79070-900, Brazil.
  • 5 Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café s/n Monte Alegre, CEP 14040-903, Ribeirão Preto, SP, Brazil.
  • 6 Laboratório de Cristalografia de Proteínas, Departamento de Ciências BioMoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café s/n Monte Alegre, CEP 14040-903, Ribeirão Preto, SP, Brazil.
  • 7 Núcleo de Pesquisas em Produtos Naturais e Sintéticos, Departamento de Ciências Biomoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café s/n Monte Alegre, Ribeirão Preto, SP, CEP 14040-903, Brazil.
  • 8 Laboratório de Síntese e Química Medicinal (LASQUIM), Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grossso do Sul- UFMS, Campo Grande, Mato Grosso do Sul, CEP 79051-470, Brazil. Electronic address: [email protected].
PMID: 37573209 DOI: 10.1016/j.ejmech.2023.115451
Abstract

Chagas disease and leishmaniasis are neglected diseases of high priority as a public health problem. Pharmacotherapy is based on the administration of a few drugs, which exhibit hazardous adverse effects and toxicity to the patients. Thus, the search for new antitrypanosomatid drugs is imperative to overcome the limitations of the treatments. In this work, 46 2-nitroimidazole 3,5-disubstituted isoxazole compounds were synthesized in good yields by [3 + 2] cycloaddition reaction between terminal acetylene (propargyl-2-nitroimidazole) and chloro-oximes. The compounds were non-toxic to LLC-MK2 cells. Compounds 30, 35, and 44 showed in vitro antichagasic activity, 15-fold, 12-fold, and 10-fold, respectively, more active than benznidazole (BZN). Compounds 30, 35, 44, 45, 53, and 61 acted as substrates for the TcNTR enzyme, indicating that this might be one of the mechanisms of action involved in their antiparasitic activity. Piperazine series and 4-monosubstituted compounds were potent against T. cruzi parasites. Besides the in vitro activity observed in compound 45, the in vivo assay showed that the compound only reduced the parasitemia levels by the seventh-day post-infection (77%, p > 0.001) compared to the control group. However, 45 significantly reduced the Parasite load in cardiac tissue (p < 0.01) 11 days post-infection. Compounds 49, 52, and 54 showed antileishmanial activity against intracellular amastigotes of Leishmania (L.) amazonensis at the same range as amphotericin B. These findings highlight the antitrypanosomatid properties of 2-nitroimidazole 3,5-disubstituted isoxazole compounds and the possibility in using them as antitrypanosomatid agents in further studies.

Keywords

Antichagasic activity; Antileishmanial activity; Bioisosterism; In vivo therapeutic effect; Nitroredutases.

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