2. Academic Validation
  3. Conjugation of N-acylhydrazone and 1,2,4-oxadiazole leads to the identification of active antimalarial agents

Conjugation of N-acylhydrazone and 1,2,4-oxadiazole leads to the identification of active antimalarial agents

  • Bioorg Med Chem. 2016 Nov 15;24(22):5693-5701. doi: 10.1016/j.bmc.2016.09.013.
José Maurício Dos Santos Filho 1,  Diogo Manoel Alves de Queiroz E Silva 2,  Taís Soares Macedo 3,  Helena Mariana Pitangueira Teixeira 3,  Diogo Rodrigo Magalhaes Moreira 3,  Soura Challal 4,  Jean-Luc Wolfender 4,  Emerson Ferreira Queiroz 4,  Milena Botelho Pereira Soares 5
Affiliations

Affiliations

  • 1 Laboratory of Design and Synthesis Applied to Medicinal Chemistry-SintMed®, Centro de Tecnologia e Geociências, Universidade Federal de Pernambuco, CEP 50740-521 Recife, PE, Brazil. Electronic address: mauricio_santosfilho@yahoo.com.br.
  • 2 Laboratory of Design and Synthesis Applied to Medicinal Chemistry-SintMed®, Centro de Tecnologia e Geociências, Universidade Federal de Pernambuco, CEP 50740-521 Recife, PE, Brazil.
  • 3 Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710 Salvador, BA, Brazil.
  • 4 School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, 30 quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland.
  • 5 Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710 Salvador, BA, Brazil; Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, CEP 41253-190 Salvador, BA, Brazil.
PMID: 27667552 DOI: 10.1016/j.bmc.2016.09.013
Abstract

Malaria, caused by several Plasmodium species, is the major life-threatening parasitic Infection worldwide. Due to the Parasite resistance to quinoline based drugs, the search for antimalarial agents is necessary. Here, we report the structural design, synthesis and antiparasitic evaluation of two novel series of 1,2,4-oxadiazoles in conjugation to N-acylhydrazones, both groups recognized as privileged structures, as well as the studies on the antimalarial activity of 16 previous described analogues. By varying substituents attached to the phenyl ring, it was possible to retain, enhance or increase the antiparasitic activity in comparison to the nonsubstituted derivatives. Replacement of substituted aryl rings by ferrocenyl and cinnamyl moieties attached in the N-acylhydrazone ablated the antiparasitic response, evidencing the structural features associated with the activity. Active compounds exhibited in vitro potency similar to mefloquine, but not all inhibited β-hematin formation. Additionally, the active compounds displayed low cytotoxicity in HepG2 cells and did not cause hemolysis in uninfected erythrocytes. In Plasmodium berghei-infected mice, the compounds reduced parasitemia but exhibited limited efficacy in increasing mice survival when compared to chloroquine, suggesting that pharmacological improvement is still necessary.

Keywords

1,2,4-Oxadiazoles; Drug design; Malaria; N-Acylhydrazones; Plasmodium falciparum.

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