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 beta-hematin inhibitory activity assay, and did not show inhibitory activity against 14-alpha-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.

Gemma, S., Campiani, G., Butini, S., Kukreja, G., Coccone, S., Joshi, B., et al. (2008). Clotrimazole scaffold as an innovative pharmacophore towards potent antimalarial agents: Design, synthesis, and 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, and biological and structure-activity relationship studies

COLETTA, MASSIMILIANO;MARINI, STEFANO;
2008-03-01

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 beta-hematin inhibitory activity assay, and did not show inhibitory activity against 14-alpha-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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10
English
Con Impact Factor ISI
chloroquine; clotrimazole; cytochrome P450; hematin; heme; sterol 14alpha demethylase; animal experiment; animal model; antimalarial activity; article; cell line; controlled study; cost benefit analysis; drug design; drug synthesis; female; malaria; matrix attachment region; mouse; nonhuman; pharmacophore; Plasmodium chabaudi; structure activity relation; toxicity; Animals; Antifungal Agents; Antimalarials; Cell Line; Clotrimazole; Cytochrome P-450 Enzyme System; Drug Design; Female; Ferric Compounds; Heme; Humans; Mice; Models, Molecular; Oxidoreductases; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium chabaudi; Plasmodium falciparum; Protoporphyrins; Stereoisomerism; Structure-Activity Relationship
Gemma, S., Campiani, G., Butini, S., Kukreja, G., Coccone, S., Joshi, B., et al. (2008). Clotrimazole scaffold as an innovative pharmacophore towards potent antimalarial agents: Design, synthesis, and biological and structure-activity relationship studies. JOURNAL OF MEDICINAL CHEMISTRY, 51(5), 1278-1294 [10.1021/jm701247k].
Gemma, S; Campiani, G; Butini, S; Kukreja, G; Coccone, S; Joshi, B; Persico, M; Nacci, V; Fiorini, I; Novellino, E; Fattorusso, E; Taglialatela Scafati, O; Savini, L; Taramelli, D; Basilico, N; Parapini, S; Morace, G; Yardley, V; Croft, S; Coletta, M; Marini, S; Fattorusso, C
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/41187
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