Combining 4-aminoquinoline- and clotrimazole-based pharmacophores toward innovative and potent hybrid antimalarials

Gemma, S. and Campiani, G. and Butini, S. and Joshi, B. P. and Kukreja, G. and Coccone, S. S. and Bernetti, M. and Persico, M. and Nacci, V. and Fiorini, I. and Novellino, E. and Taramelli, D. and Basilico, N. and Parapini, S. and Yardley, V. and Croft, S. and Keller-Maerki S., and Rottmann, M. and Brun, R. and Coletta, M. and Marini, S. and Guiso, G. and Caccia, S. and Fattorusso, C.. (2009) Combining 4-aminoquinoline- and clotrimazole-based pharmacophores toward innovative and potent hybrid antimalarials. Journal of Medicinal Chemistry, 52 (2). pp. 502-513.

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Official URL: http://edoc.unibas.ch/dok/A5843171

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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
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:13 Sep 2018 14:22
Deposited On:14 Sep 2012 06:41

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