title: N-Cinnamoylation of Antimalarial Classics: Effects of Using Acyl Groups Other than Cinnamoyl toward Dual-Stage Antimalarials.
abstract: In a follow-up study to our reports of N-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei, we decided to investigate the effect of replacing the cinnamoyl moiety with other acyl groups. Thus, a series of N-acylated analogues were synthesized, and their activities against blood- and liver-stage Plasmodium spp. were assessed along with their in vitro cytotoxicities. Although the new N-acylated analogues were found to be somewhat less active and more cytotoxic than their N-cinnamoylated counterparts, they equally displayed nanomolar activities in vitro against blood-stage drug-sensitive and drug-resistant P. falciparum, and significant in vitro liver-stage activity against P. berghei. Therefore, it is demonstrated that simple N-acylated surrogates of classical antimalarial drugs are promising dual-stage antimalarial leads.
authors.affiliation: CICECO, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro (Portugal).
authors.forename: Ana
authors.initials: A
authors.lastname: Gomes
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal).
authors.forename: Marta
authors.initials: M
authors.lastname: Machado
authors.affiliation: Centro de Malária e Outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, R. da Junqueira 100, 1349-008 Lisboa (Portugal).
authors.forename: Lis
authors.initials: L
authors.lastname: Lobo
authors.affiliation: Centro de Malária e Outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, R. da Junqueira 100, 1349-008 Lisboa (Portugal).
authors.forename: Fátima
authors.initials: F
authors.lastname: Nogueira
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal).
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.affiliation: CICECO, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro (Portugal). teixeira@ua.pt.
authors.forename: Cátia
authors.initials: C
authors.lastname: Teixeira
authors.affiliation: UCIBIO-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto (Portugal). pgomes@fc.up.pt.
authors.forename: Paula
authors.initials: P
authors.lastname: Gomes
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D002934:Cinnamates / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D011796:Quinacrine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D002934:Cinnamates; C037551:cinnamoyl chloride; D002738:Chloroquine; D011796:Quinacrine
keywords: antimalarial drugs; chloroquine; cinnamic acid; malaria; quinacrine