Endoperoxide derivatives from marine organisms: 1,2-dioxanes of the plakortin family as novel antimalarial agents.
Plakortin (1) is a remarkably simple 1,2-dioxane derivative, extracted from the marine sponge Plakortis simplex, showing a submicromolar activity against chloroquine-resistant strains of Plasmodium falciparum. Using plakortin as a novel antimalarial hit, we have prepared a series of semisynthetic derivatives in order to gain insights into the structural requirements of simple 1,2-dioxanes for exhibiting antimalarial activity. Their synthesis, spectroscopic and computational analysis, and in vitro antimalarial activity are herein reported. Results obtained, besides confirming the crucial role of the cycloperoxide functionality, revealed other structural features critical for antimalarial activity, namely the "Western" alkyl side chain, the dioxane ring conformation, and the absolute configuration of the stereogenic carbons on the 1,2-dioxane ring, when affecting the bioactive ring conformation.
Fattorusso
Caterina
C
Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
Campiani
Giuseppe
G
Catalanotti
Bruno
B
Persico
Marco
M
Basilico
Nicoletta
N
Parapini
Silvia
S
Taramelli
Donatella
D
Campagnuolo
Claudio
C
Fattorusso
Ernesto
E
Romano
Adriana
A
Taglialatela-Scafati
Orazio
O
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004351:Drug Resistance; D008958:Models, Molecular; D008968:Molecular Conformation; D047229:Plakortis / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
D000962:Antimalarials; D004146:Dioxanes