2. Academic Validation
  3. Synthesis, biological activity, and mechanism of action of new 2-pyrimidinyl hydrazone and N-acylhydrazone derivatives, a potent and new classes of antileishmanial agents

Synthesis, biological activity, and mechanism of action of new 2-pyrimidinyl hydrazone and N-acylhydrazone derivatives, a potent and new classes of antileishmanial agents

  • Eur J Med Chem. 2019 Dec 15:184:111742. doi: 10.1016/j.ejmech.2019.111742.
Elaine Soares Coimbra 1,  Marcus Vinícius Nora de Souza 2,  Mariana Sequetto Terror 1,  Alessandra Campbell Pinheiro 3,  Juliana da Trindade Granato 1
Affiliations

Affiliations

  • 1 Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, 36036-900, Juiz de Fora, Minas Gerais, Brazil.
  • 2 Fundação Oswaldo Cruz, Instituto de Tecnologia Em Fármacos-Far Manguinhos, 21041-250, Rio de Janeiro, RJ, Brazil. Electronic address: marcos_souza@far.fiocruz.br.
  • 3 Fundação Oswaldo Cruz, Instituto de Tecnologia Em Fármacos-Far Manguinhos, 21041-250, Rio de Janeiro, RJ, Brazil.
PMID: 31605866 DOI: 10.1016/j.ejmech.2019.111742
Abstract

In this work, we report the antileishmanial activity of 15 compounds based on 2-pyrimidinyl hydrazone and N-acylhydrazone derivatives, being 13 new compounds. All compounds were tested against promastigotes and Leishmania amazonensis-GFP amastigotes, as well as murine macrophages. Besides, studies about the mechanism of action of the best antileishmanial compounds and in silico physicochemical and pharmacokinetic properties were performed. Studies about the mechanism of action of representative compounds of each class showed slight differences in mode of action and both are able to cause mitochondrial depolarization and increase of intracellular ROS levels. Through computational tool and further analysis of the physicochemical and pharmacokinetic parameters, the results indicating good oral bioavailability. These results confirm the potential of 2-pyrimidinyl derivatives as lead compounds in antileishmanial drug discovery.

Keywords

Antileishmanial activity; Hydrazone and N-acylhydazones; Mechanism of action; Mitochondrial depolarization; Pyrimidinyl nucleus.

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