title: Design, synthesis, and structure-activity relationship studies of 4-quinolinyl- and 9-acrydinylhydrazones as potent antimalarial agents.
abstract: Malaria is a major health problem in poverty-stricken regions where new antiparasitic drugs are urgently required at an affordable price. We report herein the design, synthesis, and biological investigation of novel antimalarial agents with low potential to develop resistance and structurally based on a highly conjugated scaffold. Starting from a new hit, the designed modifications were performed hypothesizing a specific interaction with free heme and generation of radical intermediates. This approach provided antimalarials with improved potency against chloroquine-resistant plasmodia over known drugs. A number of structure-activity relationship (SAR) trends were identified and among the analogues synthesized, the pyrrolidinylmethylarylidene and the imidazole derivatives 5r, 5t, and 8b were found as the most potent antimalarial agents of the new series. The mechanism of action of the novel compounds was investigated and their in vivo activity was assessed.
authors.affiliation: campiani@unisi.it.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Gagan
authors.initials: G
authors.lastname: Kukreja
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Romano
authors.forename: Maria
authors.initials: M
authors.lastname: Altarelli
authors.forename: Sindu
authors.initials: S
authors.lastname: Ros
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.forename: Luisa
authors.initials: L
authors.lastname: Savini
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fattorusso
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Simon
authors.initials: S
authors.lastname: Croft
authors.forename: Marianna
authors.initials: M
authors.lastname: Borriello
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D015195:Drug Design; D004351:Drug Resistance; D006420:Hemeproteins / Q000037:antagonists & inhibitors; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007624:KB Cells; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008968:Molecular Conformation; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D000962:Antimalarials; D006420:Hemeproteins; D006835:Hydrazones; D011804:Quinolines; C020753:hemozoin; D002738:Chloroquine