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Synthesis and antimalarial evaluation of artesunate-polyamine and trioxolane-polyamine conjugates

Pearce, A. Norrie and Kaiser, Marcel and Copp, Brent R.. (2017) Synthesis and antimalarial evaluation of artesunate-polyamine and trioxolane-polyamine conjugates. European journal of medicinal chemistry, 140. pp. 595-603.

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Official URL: http://edoc.unibas.ch/58033/

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Abstract

A series of artesunate-polyamine and trioxolane-polyamine conjugates have been prepared. The conjugates were evaluated for antimalarial activity towards the K1 dual drug resistant and NF54 chloroquine-sensitive strains of Plasmodium falciparum (Pf) and for cytotoxicity towards the rat myoblast cell line L6. (Bis)-Boc-(bis)-artesunate-polyamine and (tetra)-artesunate-polyamine conjugates exhibited potent in vitro activity towards both strains of Pf, with IC50 values in the range of 0.3-1.1 nM, comparable to the parent artesunate. Cytotoxicity within this series of analogues typically increased with polyamine (PA) chain length, identifying the PA3-4-3 (spermine), and to some extent the PA3-7-3 series, as being highly selective towards the parasite. The corresponding series of (bis)-Boc-(bis)-trioxolane and (tetra)-trioxolane-polyamine conjugates were less active as antimalarials than the parent trioxolane acid, highlighting the limitation of using this warhead for drug-conjugate studies. Preliminary in vivo evaluation of two artesunate-polyamine conjugates 11 and 16 demonstrated 95.5-99.8% reduction in parasitaemia with maximal 30 day survival rates (ip delivery). Oral testing of 11 proved less efficacious, with 95.7% activity and inconsistent survival rates of 16-30 days. In contrast, trioxolane-polyamines were substantially less effective (ip delivery), exhibiting only modest reductions in parasitaemia and modest to no increase in survival rates.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0223-5234
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:02 Feb 2018 09:11
Deposited On:02 Feb 2018 09:11

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