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

• Published in: ChemMedChem 2017-12, Vol.12 (24), p.2086-2093
• Main Authors: Harmse, Rozanne, Coertzen, Dina, Wong, Ho Ning, Smit, Frans J., van der Watt, Mariette E., Reader, Janette, Nondaba, Sindiswe H., Birkholtz, Lyn‐Marie, Haynes, Richard K., N'Da, David D.
• Format: Article
• Language: English
• Subjects: Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Artemether; Artemisinin; Artemisinins - chemical synthesis; Artemisinins - chemistry; Artemisinins - pharmacology; Artesunate; azaartemisinin; Derivatives; Dihydroartemisinin; Dose-Response Relationship, Drug; Drug resistance; Fetuses; Fibroblasts; Foreskin; Gametocytes; Humans; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Lungs; Malaria; Male; Metabolism; Molecular Conformation; Parasite resistance; Parasites; Parasitic Sensitivity Tests; Plasmodium falciparum; Plasmodium falciparum - drug effects; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology; transmission; Vector-borne diseases
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700599

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 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. Resistance fighters: New artemisinin antimalarial drugs that do not provide dihydroartemisinin upon hydrolysis or metabolism and that are active against transmissible blood stages of the malaria parasite are urgently required. We examined 11‐azaartemisinin and sulfonyl derivatives, some of which possess low‐nanomolar activities against the transmissible late‐stage gametocytes of Plasmodium falciparum.