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

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.