Conjugation of N-acylhydrazone and 1,2,4-oxadiazole leads to the identification of active antimalarial agents.
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.
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.
José Maurício
JM
Dos Santos Filho
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.
Diogo Manoel Alves
DMA
de Queiroz E Silva
Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710 Salvador, BA, Brazil.
Taís Soares
TS
Macedo
Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710 Salvador, BA, Brazil.
Helena Mariana Pitangueira
HMP
Teixeira
Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710 Salvador, BA, Brazil.
Diogo Rodrigo Magalhaes
DRM
Moreira
School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, 30 quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland.
Soura
S
Challal
School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, 30 quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland.
Jean-Luc
JL
Wolfender
School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, 30 quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland.
Emerson Ferreira
EF
Queiroz
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.
Milena Botelho Pereira
MBP
Soares
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D006835:Hydrazones; D010069:Oxadiazoles
1,2,4-Oxadiazoles; Drug design; Malaria; N-Acylhydrazones; Plasmodium falciparum