Polyamine diamide orthidine F as a potent and selective antimalarial lead compound

Abstract

THE POLYAMINE DIAMIDE ORTHIDINE F AS A POTENT AND SELECTIVE ANTIMALARIAL LEAD COMPOUND Orthidine F (1) was isolated from an extract of the marine organism Aplidium orthium, found at Three Kings Islands, New Zealand.1 An initial screen of the natural product 1 against a panel of parasitic protozoa (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum K1 dual drug-resistant strain) identified selective inhibitory activity for T. brucei rhodesiense (IC50 78 μM) against T. cruzi, no detectable activity towards L. donovani and moderate activity against P. falciparum. Furthermore, the natural product was found to be non-toxic in the non-malignant L6 rat myoblast cell line, thus representing an attractive target as an antiparasitic drug. A preliminary structure-activity relationship (SAR) study identified analogues with a similar activity profile to the natural product. The analogues were found to exhibit moderate inhibitory activity against T. brucei rhodesiense (IC50 3.2–210 μM), more potent inhibitory activity against P. falciparum (IC50 0.0086–0.61 μM), and no significant activity against T. cruzi and L. donovani. The analogues also continued to display little or no cytotoxic effect in the L6 cell line, this combined with the potent IC50 values obtained for inhibition of P. falciparum afforded a series of analogues with impressive properties which warranted further studies. This led to a second series of analogues with the intention of improving its antimalarial activity. The analogues generated from this exercise exhibited potent in vitro activities (IC50 0.0086–0.61 μM) while retaining selectivity against P. falciparum. Three analogues were selected based on the in vitro data obtained and evaluated for in vivo activity in the Plasmodium berghei mouse model of malaria; which in this instance did not yield significant activity.