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 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.
Wright
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AD
Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, Bonn 53115, Germany. a.wright@uni-bonn.de
Wang
H
H
Gurrath
M
M
König
G M
GM
Kocak
G
G
Neumann
G
G
Loria
P
P
Foley
M
M
Tilley
L
L
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D006418:Heme / Q000737:chemistry* / Q000378:metabolism; D006420:Hemeproteins / Q000737:chemistry / Q000378:metabolism; D013058:Mass Spectrometry; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D009792:Oceans and Seas; D011161:Porifera / Q000737:chemistry*; D011721:Pyrenes / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013729:Terpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology
D000962:Antimalarials; D006420:Hemeproteins; D009570:Nitriles; D011721:Pyrenes; D013141:Spiro Compounds; D013729:Terpenes; C020753:hemozoin; D006418:Heme; C424432:axisonitrile 3; C424431:diisocyanoadociane