title: Evaluation of antimalarial activity and toxicity of a new primaquine prodrug.
abstract: Plasmodium vivax is the most prevalent of the five species causing malaria in humans. The current available treatment for P. vivax malaria is limited and unsatisfactory due to at least two drawbacks: the undesirable side effects of primaquine (PQ) and drug resistance to chloroquine. Phenylalanine-alanine-PQ (Phe-Ala-PQ) is a PQ prodrug with a more favorable pharmacokinetic profile compared to PQ. The toxicity of this prodrug was evaluated in in vitro assays using a human hepatoma cell line (HepG2), a monkey kidney cell line (BGM), and human red blood cells deficient in the enzyme glucose-6-phosphate-dehydrogenase (G6PD). In addition, in vivo toxicity assays were performed with rats that received multiple doses of Phe-Ala-PQ to evaluate biochemical, hematological, and histopathological parameters. The activity was assessed by the inhibition of the sporogonic cycle using a chicken malaria parasite. Phe-Ala-PQ blocked malaria transmission in Aedes mosquitoes. When compared with PQ, it was less cytotoxic to BGM and HepG2 cells and caused less hemolysis of G6PD-deficient red blood cells at similar concentrations. The prodrug caused less alteration in the biochemical parameters than did PQ. Histopathological analysis of the liver and kidney did show differences between the control and Phe-Ala-PQ-treated groups, but they were not statistically significant. Taken together, the results highlight the prodrug as a novel lead compound candidate for the treatment of P. vivax malaria and as a blocker of malaria transmission.
authors.affiliation: Departamento de Princípios Ativos Naturais e Toxicologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista - UNESP, Araraquara, São Paulo, Brazil.
authors.forename: Marcelo Gomes
authors.initials: MG
authors.lastname: Davanço
authors.affiliation: Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Anna Caroline Campos
authors.initials: AC
authors.lastname: Aguiar
authors.affiliation: Departamento de Fisiologia e Patologia, Faculdade de Odontologia de Araraquara, Universidade Estadual Paulista - UNESP, Araraquara, São Paulo, Brazil.
authors.forename: Leandro Alves
authors.initials: LA
authors.lastname: Dos Santos
authors.affiliation: Departamento de Princípios Ativos Naturais e Toxicologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista - UNESP, Araraquara, São Paulo, Brazil.
authors.forename: Elias Carvalho
authors.initials: EC
authors.lastname: Padilha
authors.affiliation: Departamento de Princípios Ativos Naturais e Toxicologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista - UNESP, Araraquara, São Paulo, Brazil.
authors.forename: Michel Leandro
authors.initials: ML
authors.lastname: Campos
authors.affiliation: Departamento de Fisiologia e Patologia, Faculdade de Odontologia de Araraquara, Universidade Estadual Paulista - UNESP, Araraquara, São Paulo, Brazil.
authors.forename: Cleverton Roberto
authors.initials: CR
authors.lastname: de Andrade
authors.affiliation: Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista - UNESP, Araraquara, São Paulo, Brazil.
authors.forename: Luiz Marcos
authors.initials: LM
authors.lastname: da Fonseca
authors.affiliation: Laboratório de Pesquisa e Desenvolvimento de Fármacos - Lapdesf, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista - UNESP, Araraquara, São Paulo, Brazil.
authors.forename: Jean Leandro
authors.initials: JL
authors.lastname: Dos Santos
authors.affiliation: Laboratório de Pesquisa e Desenvolvimento de Fármacos - Lapdesf, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista - UNESP, Araraquara, São Paulo, Brazil.
authors.forename: Chung Man
authors.initials: CM
authors.lastname: Chin
authors.affiliation: Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Antoniana Ursine
authors.initials: AU
authors.lastname: Krettli
authors.affiliation: Departamento de Princípios Ativos Naturais e Toxicologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista - UNESP, Araraquara, São Paulo, Brazil.
authors.forename: Rosangela Gonçalves
authors.initials: RG
authors.lastname: Peccinini
mesh_terms: D000330:Aedes / Q000469:parasitology; D000818:Animals; D000962:Antimalarials / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002738:Chloroquine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D004151:Dipeptides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D016780:Malaria, Vivax / Q000188:drug therapy; D008297:Male; D010964:Plasmodium gallinaceum / Q000187:drug effects; D010966:Plasmodium vivax / Q000187:drug effects; D011319:Primaquine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011355:Prodrugs / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000962:Antimalarials; D004151:Dipeptides; C578690:Phe-Ala-PQ; D011355:Prodrugs; D002738:Chloroquine; D005954:Glucosephosphate Dehydrogenase; D011319:Primaquine