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

27 Dec 2012

Diego González Cabrera, Frederic Douelle, Yassir Younis, Tzu-Shean Feng, Claire Le Manach, Aloysius T. Nchinda, Leslie J. Street, Christian Scheurer, Jolanda Kamber, Karen L. White, Oliver D. Montagnat, Eileen Ryan, Kasiram Katneni, K. Mohammed Zabiulla, Jayan T. Joseph, Sridevi Bashyam, David Waterson, Michael J. Witty, Susan A. Charman, Sergio Wittlin, and Kelly Chibale

Journal of Medicinal Chemistry
DOI: 10.1021/jm301476b


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.

View the full article on the ACS Publications website.