title: Combining 4-aminoquinoline- and clotrimazole-based pharmacophores toward innovative and potent hybrid antimalarials.
abstract: Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a-l and 5a-c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.
authors.affiliation: European Research Centre for Drug Discovery and Development and Dipartimento Farmaco Chimico Tecnologico, Universita di Siena, Via Aldo Moro, 53100 Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Joshi
authors.forename: Gagan
authors.initials: G
authors.lastname: Kukreja
authors.forename: Salvatore Sanna
authors.initials: SS
authors.lastname: Coccone
authors.forename: Matteo
authors.initials: M
authors.lastname: Bernetti
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Simon
authors.initials: S
authors.lastname: Croft
authors.forename: Sonja
authors.initials: S
authors.lastname: Keller-Maerki
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Coletta
authors.forename: Stefano
authors.initials: S
authors.lastname: Marini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Guiso
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D003022:Clotrimazole / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010961:Plasmodium / Q000187:drug effects; D051381:Rats; D013045:Species Specificity; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D003022:Clotrimazole; C001920:4-aminoquinoline