Imidazolopiperazines: hit to lead optimization of new antimalarial agents

Wu, T. and Nagle, A. and Kuhen, K. and Gagaring, K. and Borboa, R. and Francek, C. and Chen, Z. and Plouffe, D. and Goh, A. and Lakshminarayana, S. B. and Wu, J. and Ang, H. Q. and Zeng, P. and Kang, M. L. and Tan, W. and Tan, M. and Ye, N. and Lin, X. and Caldwell, C. and Ek, J. and Skolnik, S. and Liu, F. and Wang, J. and Chang, J. and Li, C. and Hollenbeck, T. and Tuntland, T. and Isbell, J. and Fischli, C. and Brun, R. and Rottmann, M. and Dartois, V. and Keller, T. and Diagana, T. and Winzeler, E. and Glynne, R. and Tully, D. C. and Chatterjee, A. K.. (2011) Imidazolopiperazines: hit to lead optimization of new antimalarial agents. Journal of medicinal chemistry, 54 (14). pp. 5116-5130.

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Official URL: http://edoc.unibas.ch/dok/A6002237

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Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug 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 and Rottmann, Matthias
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 14:26
Deposited On:11 Oct 2012 15:30

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