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

Autor: Harmse R; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa., Coertzen D; Department of Biochemistry, Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, 0002, South Africa., Wong HN; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa., Smit FJ; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa., van der Watt ME; Department of Biochemistry, Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, 0002, South Africa., Reader J; Department of Biochemistry, Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, 0002, South Africa., Nondaba SH; Department of Biochemistry, Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, 0002, South Africa., Birkholtz LM; Department of Biochemistry, Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, 0002, South Africa., Haynes RK; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa., N'Da DD; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2017 Dec 19; Vol. 12 (24), pp. 2086-2093. Date of Electronic Publication: 2017 Dec 08.
DOI: 10.1002/cmdc.201700599
Abstrakt: 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 IC 50 values <10.5 nm. The p-trifluoromethylbenzenesulfonyl-11-azaartemisinin derivative 11 [(4'-trifluoromethyl)benzenesulfonylazaartemisinin] was the most active, with IC 50 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 IC 50 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.
(© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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