Synthesis of Antimalarial Cyclopeptides by On-Resin Macrocyclization

Cyclic peptides have demonstrated advantageous properties as candidates for drug discovery. As part of a search for compounds with antimalarial activity, we have previously obtained cyclohexapeptides containing threonine/serine amino acids showing submicromolar EC50.1
In this work, the synthesis of new cyclopeptides containing Glu, instead of Thr or Ser, using SPPS (solid phase peptide synthesis) and on-resin macrocyclization, will be presented. The compounds were obtained in very good yields and purities.
In addition, in vitro cytotoxicities against Plasmodium falciparum and HepG2 cells were evaluated. Several compounds showed selective toxicity against malaria parasite (EC50 nanomolar). Moreover, a suppressive parasite growth test was used with P. berghei, NK65 strain infected mice to evaluate one cyclohexapeptide.2 This compound was active in vivo reducing the parasitemia of infected animals after 3 days of oral treatment.