Antimalarial and anticancer activities of artemisinin–quinoline hybrid-dimers and pharmacokinetic properties in mice

Malaria, one of the three most important life-threatening infectious diseases, is recommended to be treated with ACT (artemisinin combination therapy) against which Plasmodium falciparum already displayed resistance. Two artemisinin-4-amino-quinoline hybrid-dimers (1 and 2), previously synthesized, possessed low nanomolar in vitro antiplasmodial activity, while poorly toxic against mammalian cells. They are here investigated to ascertain whether this antimalarial activity would be carried on in vivo against Plasmodium vinckei. During the four day treatment, parasitemia of less than 1% were observed on day 5 after doses from 2.5 mg/kg ip and 50 mg/kg po for hybrid-dimer 1, and from 7.5 mg/kg ip and 25 mg/kg po for hybrid-dimer 2. Snapshot pharmacokinetic analysis demonstrated that the antiplasmodial activity of these C-10-acetal artemisinin dimers may be due to active metabolites, which were confirmed by in silico findings. Hybrid-dimer 1 also displayed potent in vitro activity against tumor cells and was found to be more active than etoposide against TK10, UACC62 and MCF7 cell lines (TGI values 3.45 vs. 43.33 μM, 2.21 vs. 45.52 μM and 2.99 vs. >100 μM, respectively). The 1,3-diaminopropane linker, present in hybrid-dimer 1, was therefore identified as the optimum linker.

Artemisinin-aminoquinoline hybrid-dimer, containing a diaminopropane linker, displayed potent low nanomolar in vitro antimalarial activity and was further investigated determining its ED50, pharmacokinetic properties and anticancer activities.Figure optionsDownload high-quality image (97 K)Download as PowerPoint slide