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.
Taglialatela-Scafati
Orazio
O
Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, Via D. Montesano 49, I-80131 Napoli, Italy.
Fattorusso
Ernesto
E
Romano
Adriana
A
Scala
Fernando
F
Barone
Vincenzo
V
Cimino
Paola
P
Stendardo
Emiliano
E
Catalanotti
Bruno
B
Persico
Marco
M
Fattorusso
Caterina
C
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