2,4-diaminothienopyrimidines as orally active antimalarial agents

From	UK Foreign, Commonwealth & Development Office (FCDO)
Publication year	2014
Publication authors	Taylor, D.. Waterson, D.. Charman, S.A.. White, K.L.. Wittlin, S.. Chibale, K.. Douelle, F.. González Cabrera, D.. Nchinda, A.T.. Witty, M.J.. Younis, Y.. Bashyam, S.. Duffy, S.. Le Manach, C.. de Kock, C.. Feng TzuShean, Street. L.J., Paquet. T., Avery. V.M., Mohammed Zabuilla. K., Sambandan. Y., Wiesner.
Publication Type	Scientific Publication
DOI	https://doi.org/10.1021/jm401760c
Full Citation	González Cabrera, D.; Le Manach, C.; Douelle, F.; Younis, Y.; Feng TzuShean; Paquet, T.; Nchinda, A.T.; Street, L.J.; Taylor, D.; de Kock, C.; Wiesner, L.; Duffy, S.; White, K.L.; Mohammed Zabuilla, K.; Sambandan, Y.; Bashyam, S.; Waterson, D.; Witty, M.J.; Charman, S.A.; Avery, V.M.; Wittlin, S.; Chibale, K. 2,4-Diaminothienopyrimidines as Orally Active Antimalarial Agents. Journal of Medicinal Chemistry (2014) 57 (3) 1014-1022. (DOI: 10.1021/jm401760c)

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Abstract

A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure–activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series