Karavilagenin C derivatives as antimalarials.
Karavilagenin C (1), a cucurbitane-type triterpenoid, previously isolated from the aerial parts of Momordica balsamina, was acylated with different alkanoyl, aroyl and cinnamoyl chlorides/anydrides, yielding ten new mono or diesters, karavoates F (7) and H-P (8-16). Furthermore, the new compound cucurbalsaminol C (17) was isolated from the same plant. Their structures were assigned by spectroscopic methods, including 2D NMR experiments. Compounds 1 and 17 and the acyl derivatives 8-16 along with other five esters (2-6, karavoates A-E), previously prepared from 1, were evaluated for their in vitro antimalarial activity against the chloroquine-sensitive (3D7) and the chloroquine-resistant (Dd2) strains of Plasmodium falciparum. Compound 1 exhibited a moderate activity and 17 was inactive. However, a remarkable antiplasmodial activity was observed for most of karavilagenin C alkanoyl and monoaroyl/cynamoyl derivatives. Karavoates B, D, E, I, and M were the most active, displaying IC(50) values similar to those found for chloroquine, particularly against the resistant strain (IC(50) <0.6μM). Structure-activity relationships (SAR) are discussed. Moreover, the preliminary toxicity toward human cells of compounds 1-17 was also evaluated in breast cancer cell line (MCF-7). Most of the esters showed no toxicity, displaying, in general, much higher selectivity index values than those obtained for the parent compound.
iMed.UL, Faculty of Pharmacy, University of Lisbon, Av. das Forças Armadas, 1600-083 Lisbon, Portugal.
Cátia
C
Ramalhete
Dinora
D
Lopes
Joseph
J
Molnár
Silva
S
Mulhovo
Virgílio E
VE
Rosário
Maria-José U
MJ
Ferreira
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D010963:Plasmodium falciparum / Q000187:drug effects; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000962:Antimalarials; D014315:Triterpenes