title: N-cinnamoylated chloroquine analogues as dual-stage antimalarial leads.
abstract: The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity. Now, we report the synthesis and SAR analysis of an expanded series of cinnamic acid derivatives displaying remarkably high activities against both blood- and liver-stage malaria parasites. Two compounds judged most promising, based on their in vitro activity and druglikeness according to the Lipinski rules and Veber filter, were active in vivo against blood-stage rodent malaria parasites. Therefore, the compounds reported represent a new entry as promising dual-stage antimalarial leads.
authors.affiliation: Departamento de Química e Bioquímica, Faculdade de Ciências, Centro de Investigação em Química da Universidade do Porto, Universidade do Porto, R. do Campo Alegre 687, P-4169-007 Porto, Portugal.
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Pérez
authors.forename: Cátia
authors.initials: C
authors.lastname: Teixeira
authors.forename: Inês S
authors.initials: IS
authors.lastname: Albuquerque
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: José R B
authors.initials: JR
authors.lastname: Gomes
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.forename: Paula
authors.initials: P
authors.lastname: Gomes
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology*; D002934:Cinnamates / Q000737:chemistry*; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D002934:Cinnamates; C029010:cinnamic acid; D002738:Chloroquine