Lead Optimization of Imidazopyrazines: A New Class of Antimalarial with Activity on <i>Plasmodium</i> Liver Stages

Imidazopyridine <b>1</b> was identified from a phenotypic screen against <i>P. falciparum</i> (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite <i>P. yoelii</i> (Py) as well as hypnozoites of the simian parasite <i>P. cynomolgi</i> (Pc). We applied these various assays to the cell-based lead optimization of the imidazopyrazines, exemplified by <b>3</b> (KAI407), and show that optimized compounds within the series with improved pharmacokinetic properties achieve causal prophylactic activity <i>in vivo</i> and may have the potential to target the dormant stages of <i>P. vivax</i> malaria