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Clotrimazole scaffold as an innovative pharmacophore towards potent antimalarial agents: design, synthesis, and biological and structure-activity relationship studies. 2008
Sandra Gemma, and
Giuseppe Campiani, and
Stefania Butini, and
Gagan Kukreja, and
Salvatore Sanna Coccone, and
Bhupendra P Joshi, and
Marco Persico, and
Vito Nacci, and
Isabella Fiorini, and
Ettore Novellino, and
Ernesto Fattorusso, and
Orazio Taglialatela-Scafati, and
Luisa Savini, and
Donatella Taramelli, and
Nicoletta Basilico, and
Silvia Parapini, and
Giulia Morace, and
Vanessa Yardley, and
Simon Croft, and
Massimiliano Coletta, and
Stefano Marini, and
Caterina Fattorusso
Universita di Siena, Sienna, Italy.
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.
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