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, S., Campiani, G., Butini, S., Joshi, B.P., Kukreja, G., Sanna Coccone, S., et al. (2009). Combining 4-Aminoquinoline- and Clotrimazole-based Pharmacophores towards Innovative and Potent Hybrid Antimalarials. JOURNAL OF MEDICINAL CHEMISTRY, 52(2), 502-513 [10.1021/jm801352s].

Combining 4-Aminoquinoline- and Clotrimazole-based Pharmacophores towards Innovative and Potent Hybrid Antimalarials

Gemma, Sandra;Campiani, Giuseppe;Butini, Stefania;Joshi, B. P.;Kukreja, G.;Sanna Coccone, Salvatore;Bernetti, Matteo;Nacci, Vito;Fiorini, Isabella;
2009-01-01

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.
2009
Gemma, S., Campiani, G., Butini, S., Joshi, B.P., Kukreja, G., Sanna Coccone, S., et al. (2009). Combining 4-Aminoquinoline- and Clotrimazole-based Pharmacophores towards Innovative and Potent Hybrid Antimalarials. JOURNAL OF MEDICINAL CHEMISTRY, 52(2), 502-513 [10.1021/jm801352s].
File in questo prodotto:
File Dimensione Formato  
2009_jmc_malaria_ibridi.pdf

non disponibili

Tipologia: Abstract
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 976.65 kB
Formato Adobe PDF
976.65 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/19117
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo