Clotrimazole scaffold as an innovative pharmacophore towards potent antimalarial agents: Design, synthesis, and biological and structure-activity relationship studies


Gemma, S; Campiani, G; Butini, S; Kukreja, G; Coccone, SS; Joshi, BP; 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; (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). pp. 1278-1294. ISSN 0022-2623 DOI: https://doi.org/10.1021/jm701247k

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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.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
PubMed ID: 18278860
Web of Science ID: 253784900019
URI: http://researchonline.lshtm.ac.uk/id/eprint/7852

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