Activities of 11-Azaartemisinin and N-Sulfonyl Derivatives against Asexual and Transmissible Malaria Parasites.

Dihydroartemisinin (DHA), either used in its own right or as the active drug generated in vivo from the other artemisinins in current clinical use-artemether and artesunate-induces quiescence in ring-stage parasites of Plasmodium falciparum (Pf). This induction of quiescence is linked to artemisinin resistance. Thus, we have turned to structurally disparate artemisinins that are incapable of providing DHA on metabolism. Accordingly, 11-azaartemisinin 5 and selected N-sulfonyl derivatives were screened against intraerythrocytic asexual stages of drug-sensitive Pf NF54 and drug-resistant K1 and W2 parasites. Most displayed appreciable activities against all three strains, with IC50 values <10.5 nm. The p-trifluoromethylbenzenesulfonyl-11-azaartemisinin derivative 11 [(4'-trifluoromethyl)benzenesulfonylazaartemisinin] was the most active, with IC50 values between 2 and 3 nm. The compounds were screened against Pf NF54 early and transmissible late intraerythrocytic-stage gametocytes using luciferase and parasite lactate dehydrogenase (pLDH) assays. The 2'-thienylsulfonyl derivative 16 (2'-thiophenesulfonylazaartemisinin) was notably active against late-stage (IV-V) gametocytes with an IC50 value of 8.7 nm. All compounds were relatively nontoxic to human fetal lung WI-38 fibroblasts, showing selectivity indices of >2000 toward asexual parasites. Overall, the readily accessible 11-azaartemisinin 5 and the sulfonyl derivatives 11 and 16 represent potential candidates for further development, in particular for transmission blocking of artemisinin-resistant parasites.