Several ent-manoyl oxides obtained from natural
products through chemical and microbiological
procedures were tested in vitro as inhibitors of the growth of the
promastigote and amastigote
forms of Leishmania donovani. Compounds 3,
6, 7, and 15 showed significant
antileishmanial
activity.
(3S)-ent-3β-Acetoxy-12-oxo-8α,13-epoxylabda-9,14-diene
(15), whose semisynthesis is
described, totally inhibited the promastigote forms of L.
donovani at a concentration of 100
mg/mL after 24 h of incubation. Functionalization of this series
of compounds plays an
important role in the antileishmanial activity observed.
Incubation of methyl (13R)-ent-16-hydroxy-8 alpha,13-epoxylabd-14-en-18-oate [4] with Curvularia lunata yielded ent-1 beta-hydroxy [6] and ent-6 beta-hydroxy [7] derivatives, and that of methyl (13S)-ent-16-dihydroxy-8 alpha,13-epoxylabd-14-en-18-oate [5] with the same organism gave ent-11 beta-hydroxy [8], ent-6 beta-hydroxy [9], and ent-6 beta,11 beta-dihydroxy [10] derivatives. The incubation of substrates 4 and 5 with Fusarium moniliforme afforded ent-1 beta-hydroxy derivatives (6 and 14, respectively). Cunninghamella elegans produced ent-3 beta-hydroxy, ent-1 beta-hydroxy and ent-1 beta,3 beta-dihydroxy derivatives, and led to epoxidation of the double bond of the substrates. In addition, ent-3 beta,11 alpha-dihydroxy (as the acetoxy derivative 17) and ent-3 beta,11 beta-dihydroxy [12] derivatives were isolated from incubations of substrates 4 and 5, respectively. Compounds 7, 9-11, 14, 16-18, and 21 were characterized as new polyoxygenated ent-manoyl oxides.
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