Inhibition of Heme Detoxification Processes Underlies the Antimalarial Activity of Terpene Isonitrile Compounds from Marine Sponges

Abstract

A series of terpene isonitriles, isolated from marine sponges, have previously been shown to exhibit antimalarial activities. Molecular modeling studies employing 3D-QSAR with receptor modeling methodologies performed with these isonitriles showed that the modeled molecules could be used to generate a pharmacophore hypothesis consistent with the experimentally derived biological activities. It was also shown that one of the modeled compounds, diisocyanoadociane (4), as well as axisonitrile-3 (2), both of which have potent antimalarial activity, interacts with heme (FP) by forming a coordination complex with the FP iron. Furthermore, these compounds were shown to inhibit sequestration of FP into beta-hematin and to prevent both the peroxidative and glutathione-mediated destruction of FP under conditions designed to mimic the environment within the malaria parasite. By contrast, two of the modeled diterpene isonitriles, 7-isocyanoamphilecta-11(20),15-diene (12) and 7-isocyano-15-isothiocyanatoamphilecta-11(20)-ene (13), that displayed little antimalarial activity also showed little inhibitory activity in these FP detoxification assays. These studies suggest that the active isonitrile compounds, like the quinoline antimalarials, exert their antiplasmodial activity by preventing FP detoxification. Molecular dynamics simulations performed with diisocyanoadociane (4) and axisonitrile-3 (2) allowed their different binding to FP to be distinguished.

Characterization of noncovalent complexes of antimalarial agents of the artemisinin-type and Fe(III)-heme by electrospray mass spectrometry and collisional activation tandem mass spectrometry

“…The relative binding strengths between the drugs and Fe(III)-heme was assessed using lowenergy collision-induced dissociation. This approach has previously been shown to be useful in determining the structure-activity relationship of antimalarial agents, namely, terpene isonitriles [27] and neocryptolepine derivatives [28]. We demonstrate in the present work that artemisinin-type drugs form a noncovalent complex with Fe(III)-heme in vitro, which is weaker than that with quinine.…”

“…In the final solutions, water was added in order to ensure the stabilization of the ESI process. The final pH of the solutions was about 7, at which the iron atom in the heme molecule is known to be in the Fe(III) state [27]. …”

Chemical Defenses: From Compounds to Communities

“…3) from the sponge Acanthella klethra exhibited antifungal activity against Mortierella ramannianus and Penicillium chrysogenum (Fusetani et al, 1990b). Some isocyanide compounds are also toxic to parasites, and their effect on the malaria parasite Plasmodium falciparum is the best studied (Angerhofer and Pezzuto, 1992;Wright et al, 1996Wright et al, , 2001Simpson et al, 1997).…”

A New Synthetic Route to N -Benzyl Carboxamides through the Reverse Reaction of N -Substituted Formamide Deformylase

“…An isocyanide metabolite, xanthocillin, was first isolated from Penicillium notatum (8). Most isonitriles show a wide antibiotic activity spectrum and exhibit potential as possible agents with practical use (9,10). Some metabolic intermediates of some isonitriles have been elucidated through incorporation experiments (11)(12)(13)(14)(15), and the synthetic pathway involved was determined very recently (16)(17)(18)(19).…”