title: Aryl piperazine and pyrrolidine as antimalarial agents. Synthesis and investigation of structure-activity relationships.
abstract: Piperazine and pyrrolidine derivatives were synthesised and evaluated for their capacity to inhibit the growth of Plasmodium falciparum chloroquine-resistant (FCR-3) strain in culture. The combined presence of a hydroxyl group, a propane chain and a fluor were shown to be crucial for the antiplasmodial activity. Five compounds of the aryl-alcohol series inhibited 50% of parasite growth at doses ≤10 μM. The most active compound 1-(4-fluoronaphthyl)-3-[4-(4-nitro-2-trifluoromethylphenyl)piperazin-1-yl] propan-1-ol was almost 20-40 times more active on P. falciparum (IC(50): 0.5 μM) than on tumorogenic and non-tumorogenic cells. In vivo it has a very weak effect; inhibiting 35% of parasite growth only, at 10 mg/kg/day against Plasmodium berghei infected mice without any impact on survival time. In silico molecular docking study and molecular electrostatic potential calculation revealed that this compound bound to the active site of Plasmodium plasmepsin II enzyme.
authors.affiliation: Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada, University of Navarra, Pamplona, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Mendoza
authors.forename: Silvia
authors.initials: S
authors.lastname: Pérez-Silanes
authors.forename: Miguel
authors.initials: M
authors.lastname: Quiliano
authors.forename: Adriana
authors.initials: A
authors.lastname: Pabón
authors.forename: Silvia
authors.initials: S
authors.lastname: Galiano
authors.forename: Germán
authors.initials: G
authors.lastname: González
authors.forename: Giovanny
authors.initials: G
authors.lastname: Garavito
authors.forename: Mirko
authors.initials: M
authors.lastname: Zimic
authors.forename: Abraham
authors.initials: A
authors.lastname: Vaisberg
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aldana
authors.forename: Antonio
authors.initials: A
authors.lastname: Monge
authors.forename: Eric
authors.initials: E
authors.lastname: Deharo
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D006801:Humans; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000962:Antimalarials; D010879:Piperazines; D011759:Pyrrolidines