In vitro antileishmanial activity of acetogenins from Annonaceae.
Twelve acetogenins from Annonaceae were evaluated in vitro for their antileishmanial activities in order to search for new lead-compounds having antileishmanial properties. The compounds were comparatively evaluated by the 50% inhibitory concentrations (IC50) determination on promastigote forms of wild-type and four drug-resistant lines of Leishmania donovani. In addition, after testing the toxicity on mouse peritoneal macrophages, the compounds were evaluated on amastigote infected macrophages and a therapeutic index was calculated. The IC50 of the acetogenins against promastigote forms of L. donovani was in a range 4.7-47.3 microM. The most active compound was Rolliniastatin 1 (IC50 at 4.7 microM). On the intramacrophage amastigote in vitro model, only seven compounds exhibited measurable antileishmanial activity with IC50 values in a range 2.5-29.7 microM. Rollinistatin 1 was the most interesting compound with IC50 of 2.5 microM and it appears as the most promising one on the basis of therapeutic index (18.08). Isoannonacin, which is active against intramacrophagic amastigotes (IC50 of 6.2 microM) with a therapeutic index of 2.05, exhibited a strong action on drug-resistant strains (IC50 from 5.1 to 9.8 microM). Acetogenins are a new chemical series with interesting in vitro antileishmanial activity and further studies will be focused on the understanding of this selectivity in regard to the membrane and mitochondrial action using specific probes.
Raynaud-Le Grandic
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S
Laboratoire de Phytotechnologie, EA 2085, Faculté de Pharmacie, Université Picardie Jules Verne, 80037 Amiens, France.
Fourneau
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C
Laurens
A
A
Bories
C
C
Hocquemiller
R
R
Loiseau
P M
PM
D054378:Acetogenins; D000818:Animals; D029061:Annonaceae; D004352:Drug Resistance, Microbial; D005233:Fatty Alcohols / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D007893:Leishmania donovani / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D014344:Trypanocidal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D054378:Acetogenins; D005233:Fatty Alcohols; D007783:Lactones; D014344:Trypanocidal Agents