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Structure-Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines. 2015
Diego Gonzàlez Cabrera, and
Frederic Douelle, and
Claire Le Manach, and
Ze Han, and
Tanya Paquet, and
Dale Taylor, and
Mathew Njoroge, and
Nina Lawrence, and
Lubbe Wiesner, and
David Waterson, and
Michael J Witty, and
Sergio Wittlin, and
Leslie J Street, and
Kelly Chibale
Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
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.
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