Highly active ozonides selected against drug resistant malaria

Abstract

Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites.

New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum

“…In a recent study, three synthetic trioxolanes were tested in vivo against a mouse model infected with artemisinin resistant parasites and the compounds showed high efficacy in clearing the infection [ 16 ]. These results inspired the expansion of the library of compounds and further investigation of their efficacy against artemisinin-resistant (ART-R) P. falciparum strains.…”