Manadoperoxides A-D from the Indonesian sponge Plakortis cfr. simplex. Further insights on the structure-activity relationships of simple 1,2-dioxane antimalarials.
The new endoperoxyketal polyketides manadoperoxides A-D (2-5) have been isolated from the Indonesian sponge Plakortis cfr. simplex and their stereostructures established by means of spectroscopic data and semisynthetic transformations. Manadoperoxides were assayed in vitro against D10 and W2 strains of Plasmodium falciparum and showed moderate antimalarial activity compared to that of plakortin (1) and peroxyplakoric B(3) ester (9), the latter differing from manadoperoxide B only by minor structural details. This unexpected difference in the antimalarial activity has been rationalized on the basis of our recently published model for the interaction of 1,2-dioxanes with heme and production of C-centered radicals toxic to the parasite. For the manadoperoxides, either the endoperoxide linkage is inaccessible to the heme iron or the O1 radical cannot evolve to produce a C-centered radical.
Dipartimento di Chimica delle Sostanze Naturali, Universita di Napoli "Federico II", Via D. Montesano, 49, I-80131, Napoli, Italy.
Caterina
C
Fattorusso
Marco
M
Persico
Barbara
B
Calcinai
Carlo
C
Cerrano
Silvia
S
Parapini
Donatella
D
Taramelli
Ettore
E
Novellino
Adriana
A
Romano
Fernando
F
Scala
Ernesto
E
Fattorusso
Orazio
O
Taglialatela-Scafati
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004146:Dioxanes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D021261:Parasitic Sensitivity Tests; D047229:Plakortis / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D004146:Dioxanes