Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines

Diego Gonzalez Cabrera, Frederic Douelle, Yassir Younis, Tzu-Shean Feng, Claire Le Manach, Aloysius T Nchinda, Leslie J Street, Christian Scheurer, Jolanda Kamber, Karen Louise White, Oliver Daniel Montagnat, Eileen Ryan, Kasiram Katneni, Mohammed K Zabiulla, Jayan T Joseph, Sridevi Bashyam, David Waterson, Michael J Witty, Susan Ann Charman, Sergio WittlinKelly Chibale

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27 Citations (Scopus)


In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.
Original languageEnglish
Pages (from-to)11022 - 11030
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number24
Publication statusPublished - 2012

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