Structure-activity-relationship studies around the 2-amino group and pyridine core of antimalarial 3,5-diarylaminopyridines lead to a novel series of pyrazine analogues with oral in vivo activity

Yassir Younis, Frederic Douelle, Diego Gonzalez Cabrera, Claire Le Manach, Aloysius T Nchinda, Tanya Paquet, Leslie J Street, Karen Louise White, Mohammed K Zabiulla, Jayan T Joseph, Sridevi Bashyam, David Waterson, Michael J Witty, Sergio Wittlin, Susan Ann Charman, Kelly Chibale

Research output: Contribution to journalArticleResearchpeer-review

38 Citations (Scopus)


Replacement of the pyridine core of antimalarial 3,5-diaryl-2- aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC 50 values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei-infected mice, compound 4 was completely curative at an oral dose of 4 ? 10 mg/kg.
Original languageEnglish
Pages (from-to)8860 - 8871
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number21
Publication statusPublished - 2013

Cite this