Insight into the mechanism of action of plakortins, simple 1,2-dioxane antimalarials.
A multidisciplinary approach, based on molecular dynamics/mechanics, ab initio calculations, dynamic docking studies, and chemical reactions, has been employed to gain insight into the mechanism of the antimalarial action of plakortin and dihydroplakortin, simple 1,2-dioxanes isolated from the sponge Plakortis simplex. Our results show that these molecules, after interaction of the endoperoxide bond with Fe(ii), likely coming from the heme molecule, give rise to the formation of an oxygen radical, followed by rearrangement to give a carbon radical centered on the "western" alkyl side-chain. The carbon radicals generated on the side-chain, amenable for intermolecular reactions, should represent the toxic intermediates responsible for subsequent reactions leading to plasmodium death. The minimal structural requirements necessary for the activity of this class of antimalarial agents have been identified and discussed throughout the paper.
Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, Via D. Montesano 49, I-80131 Napoli, Italy.
Orazio
O
Taglialatela-Scafati
Ernesto
E
Fattorusso
Adriana
A
Romano
Fernando
F
Scala
Vincenzo
V
Barone
Paola
P
Cimino
Emiliano
E
Stendardo
Bruno
B
Catalanotti
Marco
M
Persico
Caterina
C
Fattorusso
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004146:Dioxanes / Q000737:chemistry / Q000494:pharmacology; D004147:Dioxins / Q000737:chemistry / Q000633:toxicity; D008956:Models, Chemical; D021261:Parasitic Sensitivity Tests; D047229:Plakortis / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects*; D011161:Porifera / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
D000962:Antimalarials; D004146:Dioxanes; D004147:Dioxins; C025223:1,4-dioxane