Structure-Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines

24 Sep 2015

Diego Gonzàlez Cabrera, Frederic Douelle, Claire Le Manach, Ze Han, Tanya Paquet, Dale Taylor, Mathew Njoroge, Nina Lawrence, Lubbe Wiesner, David Waterson, Michael J. Witty, Sergio Wittlin, Leslie J. Street, and Kelly Chibale

Journal of Medicinal Chemistry
DOI: 10.1021/acs.jmedchem.5b01156
Suwit Ngaokaew/


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. 

View the full article on the Journal of Medicinal Chemistry website.