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Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials : further structure-activity relationships, in vivo studies, and preliminary toxicity profiling

Gemma, S. and Camodeca, C. and Sanna, Coccone and Joshi, B. P. and Bernetti, M. and Moretti, V. and Brogi, S. and Bonache, M. C. and Savini, L. and Taramelli, D. and Basilico, N. and Parapini, S. and Rottmann, M. and Brun, R. and Lamponi, S. and Caccia, S. and Guiso, G. and Summer, R. and Martin, R. and Saponara, S. and Gorelli, B. and Novellino, E. and Campiani, G. and Butini, S.. (2012) Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials : further structure-activity relationships, in vivo studies, and preliminary toxicity profiling. Journal of medicinal chemistry, 55 (15). pp. 6948-6967.

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Official URL: http://edoc.unibas.ch/dok/A6094304

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Abstract

Despite recent progress in the fight against malaria, the emergence and spread of drug-resistant parasites remains a serious obstacle to the treatment of infections. We recently reported the development of a novel antimalarial drug that combines the 4-aminoquinoline pharmacophore of chloroquine with that of clotrimazole-based antimalarials. Here we describe the optimization of this class of hybrid drug through in depth structure-activity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasite's 'chloroquine resistance transporter' were investigated in a Xenopus laevis oocyte expression system. These tests indicated that piperazine-derivatives 4b and 4d may be suitable for co-administration with chloroquine against chloroquine-resistant parasites. The potential for metabolism of the drugs by cytochrome P450 was determined in silico and the lead compounds were tested for toxicity and mutagenicity. A preliminary pharmacokinetic analysis undertaken in mice indicated that compound 4b has an optimal half-life
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Oct 2017 07:03
Deposited On:16 Aug 2013 07:28

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