title: Development of piperazine-tethered heterodimers as potent antimalarials against chloroquine-resistant P. falciparum strains. Synthesis and molecular modeling.
abstract: The design, synthesis, and antiplasmodial activity of antimalarial heterodimers based on the 1,4-bis(3-aminopropyl)piperazine linker is reported. In this series key structural elements derived from quinoline antimalarials were coupled to fragments capable of coordinating metal ions. Biological evaluation included determination of activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. Some of the novel compounds presented high activity in vitro against chloroquine-resistant strains, more potent than chloroquine and clotrimazole. Computational studies revealed that the activity is likely due to the ability of the compounds to assume a multisite iron coordinating geometry.
authors.affiliation: European Research Centre for Drug Discovery & Development, Università di Siena, via Aldo Moro, 53100 Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Gagan
authors.initials: G
authors.lastname: Kukreja
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Matteo
authors.initials: M
authors.lastname: Bernetti
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Joshi
authors.forename: Luisa
authors.initials: L
authors.lastname: Savini
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: Alessia
authors.initials: A
authors.lastname: Bertamino
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Bruno
authors.initials: B
authors.lastname: Catalanotti
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002738:Chloroquine / Q000494:pharmacology*; D003022:Clotrimazole / Q000494:pharmacology; D019281:Dimerization; D015195:Drug Design; D004351:Drug Resistance; D007477:Ions; D008670:Metals / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D007477:Ions; D008670:Metals; D010879:Piperazines; D000077489:Piperazine; D002738:Chloroquine; D003022:Clotrimazole