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778
Vol. 29, No. 8
of the manoyl oxide derivatives, it seems that the substitution
of the side chain by a sugar (compound 47, 48) or the forma-
tion of the double bond (compound 46) has no significant im-
pact on leishmanicidal activity of the manoyl oxide skeleton.
In summary, two species from the genus Cistus contain
several non-polar bioactive compounds that are mainly diter-
penes, that possess significant antileshmanial activity. The
IC50 concentratrions of none of the compounds were as low
as those of pentamidine or amphotericin B, however, 2, 3 and
3
6 were more active than pentamidine at their I90 concentra-
Fig. 5. Natural and Semisynthetic Triterpenes
tions. In addition, the biological evaluation of a large number
of semisynthetic compounds led to the identification of some
active than the parent compound 16. Compound 16 has mod- potent derivatives and to some structure–activity relationship
erate activity but its natural acetoxy derivative 15 has activity findings that could be useful leads in the design of new,
with IC ꢂ20 mg/ml. Compounds 44—48, have a moderate highly potent antileishmanial agents.
5
0
activity (10 mg/mlꢂIC ꢂ20 mg/ml), while compounds 40—
5
0
4
2 are highly active (IC ꢂ10 mg/ml). Compound 40 was
A
cknowledgements Antileishmanial screening at NCNPR
5
0
very active with an IC of 4.3 mg/ml.
is supported under a USDA scientific cooperative agreement
5
0
The natural triterpene 12 (Fig. 5) was almost inactive (IC50 58-6408-2-0009. We thank Dr. Shabana I Khan for the evalu-
6 mg/ml), but its hydrolyzed derivative 13 was highly active ation of cytotoxicity of the compounds. We thank Professor
3
with IC 5.3 mg/ml, which is in accordance with previously Balana-Fouce, University of Leon, Spain for providing the
5
0
13)
published data.
culture of Leishmania donovani.
All natural and semisynthetic derivatives were also evalu-
ated for their cytotoxicity against VERO cells (monkey kid-
ney fibroblasts). None of them were cytotoxic to the mam-
malian cells up to the highest concentration of 47.6 mg/ml.
The structural diversity of the natural labdane type diter-
penes and semisynthetic derivatives evaluated in our studies
allows us to make some comments about structure–activity
relationships. In both cases of 13(E)-labda-7,13-dien-15-ol
and 13(E)-labd-13-ene-8a,15-diol derivatives the presence
of a carboxylic acid side chain leads to inactive compounds
REFERENCES AND NOTES
1) www.who.int/emc/diseases/leish/leisprogress.html
2)
Anders G., Eisenberger C. L., Jonas F., Greenblatt C. L., Trans. R. Soc.
Trop. Med. Hyg., 96 (Suppl. 1), S87—S92 (2002).
3
4
)
)
Kafetzis D. A., J. Postgrad. Med., 49, 31—38 (2003).
Fokialakis N., Kalpoutzakis E., Khan S. I., Tekwani B. L., Kobaisy M.,
Skaltsounis A. L., Duke S. O., J. Nat. Med., (in press).
5) Warburg E. F., “Flora Europea,” Vol. 2, Cambridge University Press,
968, pp. 282—284.
1
6
)
Kalpoutzakis E., Aligiannis N., Mitaku S., Chinou I., Charvala C.,
Skaltsounis A. L., Z. Naturforsch., 56c, 49—52 (2001).
Kalpoutzakis E., Chinou I., Mitaku S., Skaltsounis A. L., Charvala C.,
Nat. Prod. Lett., 11, 173—179 (1998).
(compare 17 to 19 and 18 to 20), and it seems that the basic
skeleton rings of the above two groups of compounds with
no substituents are more effective than the manoyl oxide
skeleton (compare compounds 19 and 20 to 16). In addition,
in all three cases the presence of a long side carbamide chain
makes the derivatives (compounds 26, 34, 43) inactive, while
a shorter carbamate chain had no negative effects (com-
7)
8) Kalpoutzakis E., Aligiannis N., Skaltsounis A. L., Mitaku S., J. Nat.
Prod., 66, 316—319 (2003).
9)
Kalpoutzakis E., Aligiannis N., Mitaku S., Chinou I., Charvala C.,
Skaltsounis A. L., Chem. Pharm. Bull., 49, 814—817 (2001).
10) Mikus J., Steverding D., Parasitol. Int., 48, 265—269 (2000).
pounds 27, 35, 44). On the other hand, the presence of the 11) Mustafa J., Khan S. I., Ma G., Walker L. A., Khan I. A., Lipids, 39,
ethylclorinated carbamate chain in all three cases increased
the activity, and in some cases afforded some of the most po-
tent semisynthetic derivatives (compounds 28, 36, 42). This
is in accordance with previous results obtained for these
167—172 (2004).
1
2) Borenfreund E., Babich H., Martin-Alguacil N., In Vitro Cell Dev.
Biol., 26, 1030—1034 (1990).
3) Torres-Santos E. C., Lopes D., Rodrigues Oliveira R., Carauta J. P. P.,
Bandeira Falcao C. A., Kaplan M. A. C., Rossi-Bergmann B., Phy-
tomedicine, 11, 114—120 (2004).
1
6,9)
compounds against a wide range of microbes. In the case