Antiplasmodial activity: The first proof of inhibition of heme crystallization by marine isonitriles

•Mode of action of potent antiplasmodial compounds.•Marine natural products inhibit heme detoxification in vitro.•Binding motif of cyclic diterpenes with heme and heme dimer.

Over a decade ago Wright et al., proposed a putative antiplasmodial mechanism of action for marine isonitriles (1, and 3–6) and isothiocyanate (2) that involved interference in heme detoxification by Plasmodium falciparum thus inhibiting the growth of the parasite. In the current paper we describe the successful down scaling of Egan's β-hematin inhibition assay for analyses of small quantities of marine natural products as potential β-hematin inhibitors. The modified assay revealed for the first time that the most active antiplasmodial marine isonitrile 4 (IC50 13 nM) totally inhibited β-hematin crystallization while 5 (IC50 31 nM) and 6 (IC50 81 nM) showed inhibition at lower levels. A cursory ab initio molecular dynamics investigation into the relative stabilities of bonded complexes between isocyanate, isothiocyanate and isonitrile groups with the iron center of heme supported our findings that these marine metabolites do indeed interfere with biocrystallization of heme.

Graphical abstractCymbastela hooperi source of antiplasmodial marine isonitriles (Left). The structure of the most potent heme polymerization inhibitor tested (Centre). SEM micrograph of hematin, showing inhibition of heme polymerization (Right).Figure optionsDownload full-size imageDownload as PowerPoint slide