Combining 4-aminoquinoline- and clotrimazole-based pharmacophores toward innovative and potent hybrid antimalarials.
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.
Gemma
Sandra
S
European Research Centre for Drug Discovery and Development and Dipartimento Farmaco Chimico Tecnologico, Universita di Siena, Via Aldo Moro, 53100 Siena, Italy.
Campiani
Giuseppe
G
Butini
Stefania
S
Joshi
Bhupendra P
BP
Kukreja
Gagan
G
Coccone
Salvatore Sanna
SS
Bernetti
Matteo
M
Persico
Marco
M
Nacci
Vito
V
Fiorini
Isabella
I
Novellino
Ettore
E
Taramelli
Donatella
D
Basilico
Nicoletta
N
Parapini
Silvia
S
Yardley
Vanessa
V
Croft
Simon
S
Keller-Maerki
Sonja
S
Rottmann
Matthias
M
Brun
Reto
R
Coletta
Massimiliano
M
Marini
Stefano
S
Guiso
Giovanna
G
Caccia
Silvio
S
Fattorusso
Caterina
C
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
D000634:Aminoquinolines; D000962:Antimalarials; D003022:Clotrimazole; C001920:4-aminoquinoline