We describe herein the design, synthesis, biological evaluation, and structure-activity relationship (SAR) studies of an innovative class of antimalarial agents based on a polyaromatic pharmacophore structurally related to clotrimazole and easy to synthesize by low-cost synthetic procedures. SAR studies delineated a number of structural features able to modulate the in vitro and in vivo antimalarial activity. A selected set of antimalarials was further biologically investigated and displayed low in vitro toxicity on a panel of human and murine cell lines. In vitro, the novel compounds proved to be selective for free heme, as demonstrated in the β-hematin inhibitory activity assay, and did not show inhibitory activity against 14-α-lanosterol demethylase (a fungal P450 cytochrome). Compounds 2, 4e, and 4n exhibited in vivo activity against P. chabaudi after oral administration and thus represent promising antimalarial agents for further preclinical development. © 2008 American Chemical Society.

Gemma, S., Campiani, G., Butini, S., Kukreja, G., Sanna Coccone, S., Joshi, B., et al. (2008). Clotrimazole Scaffold as an Innovative Pharmacophore Towards Potent Antimalarial Agents: Design, Synthesis, Biological and Structure-Activity Relationship Studies. JOURNAL OF MEDICINAL CHEMISTRY, 51(5), 1278-1294 [10.1021/jm701247k].

Clotrimazole Scaffold as an Innovative Pharmacophore Towards Potent Antimalarial Agents: Design, Synthesis, Biological and Structure-Activity Relationship Studies

Gemma, Sandra;Campiani, Giuseppe;Butini, Stefania;Joshi, B.;Nacci, Vito;Fiorini, Isabella;Savini, Luisa;
2008-01-01

Abstract

We describe herein the design, synthesis, biological evaluation, and structure-activity relationship (SAR) studies of an innovative class of antimalarial agents based on a polyaromatic pharmacophore structurally related to clotrimazole and easy to synthesize by low-cost synthetic procedures. SAR studies delineated a number of structural features able to modulate the in vitro and in vivo antimalarial activity. A selected set of antimalarials was further biologically investigated and displayed low in vitro toxicity on a panel of human and murine cell lines. In vitro, the novel compounds proved to be selective for free heme, as demonstrated in the β-hematin inhibitory activity assay, and did not show inhibitory activity against 14-α-lanosterol demethylase (a fungal P450 cytochrome). Compounds 2, 4e, and 4n exhibited in vivo activity against P. chabaudi after oral administration and thus represent promising antimalarial agents for further preclinical development. © 2008 American Chemical Society.
2008
Gemma, S., Campiani, G., Butini, S., Kukreja, G., Sanna Coccone, S., Joshi, B., et al. (2008). Clotrimazole Scaffold as an Innovative Pharmacophore Towards Potent Antimalarial Agents: Design, Synthesis, Biological and Structure-Activity Relationship Studies. JOURNAL OF MEDICINAL CHEMISTRY, 51(5), 1278-1294 [10.1021/jm701247k].
File in questo prodotto:
File Dimensione Formato  
18_2008_jm701247k_CLT.pdf

non disponibili

Tipologia: Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 805.29 kB
Formato Adobe PDF
805.29 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/11365/2521
 Attenzione

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