Activities of 11‐azaartemisinin and N‐sulfonyl derivatives against asexual and transmissible malaria parasites

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dc.contributor.author Harmse, Rozanne
dc.contributor.author Coertzen, Dina
dc.contributor.author Wong, Ho Ning
dc.contributor.author Smit, Frans J.
dc.contributor.author Van der Watt, M.E. (Mariette)
dc.contributor.author Reader, Janette
dc.contributor.author Nondaba, Sindisiwe
dc.contributor.author Birkholtz, Lyn-Marie
dc.contributor.author Haynes, Richard K.
dc.contributor.author N'Da, David
dc.date.accessioned 2018-04-06T13:18:49Z
dc.date.issued 2017-12
dc.description.abstract 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. en_ZA
dc.description.department Biochemistry en_ZA
dc.description.embargo 2018-12-19
dc.description.librarian hj2018 en_ZA
dc.description.uri http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1860-7187 en_ZA
dc.identifier.citation Harmse, R., Coertzen, D., Wong, H.N. et al. 2017, 'Activities of 11‐azaartemisinin and N‐sulfonyl derivatives against asexual and transmissible malaria parasites', ChemMedChem, vol. 12, no. 24, pp. 2086-2093. en_ZA
dc.identifier.issn 1860-7179 (print)
dc.identifier.issn 1860-7187 (online)
dc.identifier.other 10.1002/cmdc.201700599
dc.identifier.uri http://hdl.handle.net/2263/64422
dc.language.iso en en_ZA
dc.publisher Wiley en_ZA
dc.rights © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. This is the pre-peer reviewed version of the following article : 'Activities of 11‐azaartemisinin and N‐sulfonyl derivatives against asexual and transmissible malaria parasites', ChemMedChem, vol. 12, no. 24, pp. 2086-2093, 2017, doi : 10.1002/cmdc.201700599. The definite version is available at : http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1860-7187. en_ZA
dc.subject Malaria en_ZA
dc.subject Transmission en_ZA
dc.subject Gametocytes en_ZA
dc.subject Azaartemisinin en_ZA
dc.subject Artemisinin en_ZA
dc.title Activities of 11‐azaartemisinin and N‐sulfonyl derivatives against asexual and transmissible malaria parasites en_ZA
dc.type Postprint Article en_ZA


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