Inhibition of heme detoxification processes underlies the antimalarial activity of terpene isonitrile compounds from marine sponges

A series of terpene isonitriles, isolated from marine sponges, have previou sly been shown to exhibit antimalarial activities. Molecular modeling studi es employing 3D-QSAR with receptor modeling methodologies performed with th ese isonitriles showed that the modeled molecules could be used to generate a pharmacophore hypothesis consistent with the experimentally derived biol ogical activities. It was also shown that one of the modeled compounds, dii socyanoadociane (4), as well as axisonitrile-3 (2), both of which have pote nt antimalarial activity, interacts with heme (FP) by forming a coordinatio n complex with the FP iron. Furthermore, these compounds were shown to inhi bit sequestration of FP into P-hematin and to prevent both the peroxidative and glutathione-mediated destruction of FP under conditions designed to mi mic the environment within the malaria parasite. By contrast, two of the mo deled diterpene isonitriles, 7-isocyanoamphilecta-11(20),15-diene (12) and 7-isocyano-15-isothiocyanatoamphilecta-11(20)-ene (13), that displayed litt le antimalarial activity also showed little inhibitory activity in these FP detoxification assays. These studies suggest that the active isonitrile co mpounds, like the quinoline antimalarials, exert their antiplasmodial activ ity by preventing FP detoxification. Molecular dynamics simulations perform ed with diisocyanoadociane (4) and axisonitrile-3 (2) allowed their differe nt binding to FP to be distinguished.