Structural optimization of indolizinoindolones to obtain potent new antimalarials with dual stage activity

Malaria continues to represent a major public health concern due to the emergence of resistance to most available drugs. We report the optimization of the indolizinoindolone scaffold to increase activity against erythrocytic stages of Plasmodium (P.) falciparum and against hepatic stages of the rodent parasite P. berghei. Twenty-six enantiopure indolizinoindolones were synthesized, with IC₅₀ values in the low micromolar and sub-micromolar range against both stages, and no significant cytotoxicity against mammalian cell lines. The most active compound showed nanomolar activity against P. falciparum blood stages in vitro, low micromolar activity against hepatic P. berghei infection in vitro, and a 7-fold higher selectivity index than that of chloroquine. This compound was also tested in P. berghei-infected mice, inhibiting the development of parasitemia relative to untreated mice. Overall, we identified a new set of lead antimalarial compounds. Further optimization of the pharmacokinetic properties of this scaffold is warranted.