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Structure-activity relationship studies of orally active antimalarial 2,4-diamino-thienopyrimidines

Gonzàlez Cabrera, Diego and Douelle, Frederic and Le Manach, Claire and Han, Ze and Paquet, Tanya and Taylor, Dale and Njoroge, Mathew and Lawrence, Nina and Wiesner, Lubbe and Waterson, David and Witty, Michael J. and Wittlin, Sergio and Street, Leslie J. and Chibale, Kelly. (2015) Structure-activity relationship studies of orally active antimalarial 2,4-diamino-thienopyrimidines. Journal of medicinal chemistry, 58 (18). pp. 7572-7579.

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Official URL: http://edoc.unibas.ch/dok/A6438847

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Abstract

Based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. Improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously reported compounds, and with a slightly improved hERG profile.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
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 06:20
Deposited On:06 Nov 2015 10:21

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