Planta Med 2007; 73(3): 206-211
DOI: 10.1055/s-2007-967123
Original Paper
Pharmacology
© Georg Thieme Verlag KG Stuttgart · New York

Leishmanicidal Constituents from the Leaves of Piper rusbyi

Ninoska Flores1 , 2 , Gabriela Cabrera3 , Ignacio A. Jiménez1 , Jose Piñero3 , Alberto Giménez2 , Genevieve Bourdy2 , Fernando Cortés-Selva4 , Isabel L. Bazzocchi1
  • 1Instituto Universitario de Bio-Orgánica ”Antonio González”, Universidad de La Laguna, Tenerife, Canary Islands, Spain
  • 2Instituto de Investigaciones Fármaco Bioquímicas, Facultad de Ciencias Farmacéuticas y Bioquímicas, Universidad Mayor de San Andrés, La Paz, Bolivia
  • 3Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de la Laguna, Tenerife, Canary Islands, Spain
  • 4Instituto de Parasitología y Biomedicina ”López-Neyra”, Consejo Superior de Investigaciones Científicas, Armilla, Granada, Spain
Further Information

Publication History

Received: March 24, 2006

Accepted: January 17, 2007

Publication Date:
12 March 2007 (online)

Abstract

The kavapyrone (+)-(7R,8S)-epoxy-5,6-didehydrokavain (1) and the chalcone flavokavain B (2) were isolated from Piper rusbyi as the bioactive components by bioassay-guided fractionation, using an in vitro assay against promastigote forms of three Leishmania strains. In addition, the new kavapyrone, (7R,8R/7S,8S)-dihydroxy-5,6-didehydrokavain (3), which is very likely an artifact, and four known compounds (4 - 7) were isolated. Their structures were elucidated on the basis of spectral analysis, and the absolute configurations of compounds 1 and 3 were established by CD studies and the modified Mosher ester procedure, respectively. All compounds were evaluated for in vitro leishmanicidal activity. The most active compounds 1 (IC50 = 81.9 μM) and 2 (IC50 = 11.2 μM) were also evaluated in vivo against a New World strain of cutaneous leishmaniasis, and the results showed the efficacy of 2 at a dose of 5 mg/kg/day. Compounds 1 and 3 were also assayed as reversal agents against a multidrug-resistant Leishmania tropica line, but were found to be inactive.

References

  • 1 Nwaka S, Hudson A. Innovative lead discovery strategies for tropical diseases.  Nature Rev Drug Discov. 2006;  5 941-55.
  • 2 Pérez-Victoria J M, Di Prieto A, Barron D, Ravelo A G, Castanys S, Gamarro F. Multidrug resistance phenotype mediated by the P-glycoprotein-like transporter in Leishmania: a search for reversal agents.  Curr Drug Targets. 2002;  3 311-33.
  • 3 Parmar V S, Jain S C, Bisht K S, Jain R, Taneja P, Jha A. et al . Phytochemistry of the genus Piper .  Phytochemistry. 1997;  4 597-673.
  • 4 Townson S. Antiparasitic properties of medicinal plants and other naturally occurring products.  Adv Parasitol. 2001;  50 199-295.
  • 5 Piñero J E, Jiménez I A, Valladares B, Ravelo A G. Advances in leishmaniasis chemotherapy and new relevant patents.  Expert Opin Ther Patents. 2004;  14 1113-23.
  • 6 Adityachaudhury N, Das A K, Daskanungo P. Occurrence of 5,6-dehydrokawain and 7,8-epoxy-5,6-dehydrokawain in Didymocarpus aurentica .  Indian J Chem B. 1976;  14 909-11.
  • 7 Ranjith H, Dharmaratne W, Nanayakkara N P, Ikhlas A K. Kavalactones from Piper methysticum, and their 13C NMR spectroscopic analyses.  Phytochemistry. 2002;  59 429-33.
  • 8 Ramos L S, Da Silva M L, Luz A IR, Zoghi M GB, Maia J GS. Essential oil of Piper marginatum .  J Nat Prod. 1986;  49 712-3.
  • 9 Orjala J, Wright A D, Erdelmeier C AJ, Sticher O, Rali T. New monoterpene-substituted dihydrochalcones from Piper aduncum .  Helv Chim Acta. 1993;  76 1481-8.
  • 10 San Feliciano A, Medarde M, Gordaliza M, Del Olmo E, Miguel del Corral J M. Sesquiterpenoids and phenolics of Pulicaria paludosa .  Phytochemistry. 1989;  28 2717-21.
  • 11 Fuyihiko I, Akira A. Analysis of 1H and 13C Nuclear magnetic resonance spectra of sphatulenol by two-dimensional methods. J Chem Soc [Perkin 2] 1985: 1773-8.
  • 12 Deharo E, Ruiz G, Vargas F, Sagua H, Ortega E, Rojas A. et al .Técnicas de laboratorio para la selección de sustancias antichagas y leishmanicidas. La Paz; Prisa Ltda.-CYTED 2003.
  • 13 Piñero J, Temporal R M, Silva-Goncalvez A J, Jiménez I A, Bazzocchi I L, Oliva A. et al . New administration model of trans-chalcone biodegradable polymers for the treatment of experimental leishmaniasis.  Acta Trop. 2006;  98 59-65.
  • 14 Cortés-Selva F, Campillo M, Reyes C P, Jiménez I A, Castanys S, Bazzocchi I L. et al . SAR studies of dihydro-β-agarofuran sesquiterpenes as inhibitors of the multridrug-resistance phenotype in a Leishmania tropica line overexpressing a P-glycoprotein-like transporter.  J Med Chem. 2004;  47 576-87.
  • 15 Achenbach H, Low E. Synthesis of 5,6-didehydrokawain-trans-7,8-epoxide and related compounds.  Nat Prod Lett. 1997;  10 79-85.
  • 16 González A G, Nuñez M P, Ravelo A G, Sazatornil J A, Vazquéz J T, Bazzocchi I L. et al .Structural elucidation and absolute configuration of novel β-agafuran (epoxyeudesmene) sesquiterpenes from Maytenus magellanica (Celastraceae). J Chem Soc [Perkin 1] 1992: 1437-41.
  • 17 PC Model from Serena Software, P.O. Box 3076, Bloomington, IN 47 402 - 3076. 
  • 18 Gottarelli G, Samori B. Circular dichroism of (-)-S-trans-1,2-di-4-pyridyloxirane. J Chem Soc [Perkin 2] 1972 1998 - 2001.
  • 19 Bennett F, Knight D W, Fenton G. An alternative approach to mevinic acid analogues from methyl (3R)-(-)-3-hydroxyhex-5-enoate and an extension to unambiguous syntheses of (6R)-(+)- and (6S)-(-)-goniothalamin. J Chem Soc [Perkin 1] 1991: 519-23.
  • 20 Hasam C M, Mia M Y, Rashid M A, Connolly J D. 5-Acetoxyisogoniothalamin oxide, an epoxystyryl lactone from Goniothalamus sesquipedalis .  Phytochemistry. 1994;  37 1763-4.
  • 21 Shing T KM, Aloui M. The stereochemistry of the epoxypropyl side-chain of asperlin.  J Chem Soc Chem Commun. 1988;  23 1525-26.
  • 22 Seco J M, Quiñoá E, Riguera R. The assignment and absolute configuration by NMR.  Chem Rev. 2004;  104 17-117.
  • 23 Kayser O, Kiderlen A F. In vitro leishmanicidal activity of naturally occurring chalcones.  Phytother Res. 2001;  15 148-52.
  • 24 Chen M, Zhai L, Christensen S B, Theander T G, Kharazmi A. Inhibition of fumarate reductase in Leishmania major and L. donovani by chalcones.  Antimicrob Agents Chemother. 2001;  45 2023-9.
  • 25 Liu M, Wilairat P, Croft S L, Tan A L-Ch, Go M -L. Sructure-activity relationships of antileishmanial and antimalarial chalcones.  Bioorg Med Chem. 2003;  11 2729-38.
  • 26 Hermoso A, Jiménez I A, Mamani Z A, Bazzocchi I L, Piñero J E, Ravelo A G. et al . Antileishmanial activities of dihydrochalcones from Piper elongatum and synthetic related compounds. Structural requirements for activity.  Bioorg Med Chem. 2003;  11 3975-80.

Isabel López Bazzocchi

Instituto Universitario de Bio-Orgánica ”Antonio González”

Universidad de La Laguna

Avenida Astrofísico Francisco Sánchez 2

La Laguna

38206 Tenerife

Canary Islands

Spain

Phone: +34-922-318-594

Fax: +34-922-318-571

Email: ilopez@ull.es