Download PDF
Planta Med 2001; 67(7): 623-627
DOI: 10.1055/s-2001-17351
Original Paper
Pharmacology
© Georg Thieme Verlag Stuttgart · New York

In Vitro Effect of Alkaloids on Bloodstream Forms of Trypanosoma brucei and T. congolense

Karin Merschjohann1 , Frank Sporer2 , Dietmar Steverding1 , Michael Wink2,*
  • 1 Abteilung Parasitologie, Hygiene-Institut, Ruprecht-Karls Universität, Heidelberg, Germany
  • 2 Institut für Pharmazeutische Biologie, Ruprecht-Karls Universität, Heidelberg, Germany
Further Information

Publication History

September 15, 2000

December 16, 2000

Publication Date:
24 September 2001 (online)

Also available at
    Permissions and Reprints

Abstract

The effect of 34 alkaloids of the piperidine, pyridine, tropane, isoquinoline, indole, quinolizidine, quinoline, purine, and steroidal types on the growth of Trypanosoma brucei, T. congolense, and human HL-60 cells was investigated in vitro. Berbamine, berberine, cinchonidine, cinchonine, emetine, ergotamine, quinidine, quinine, and sanguinarine showed trypanocidal activities with ED50 (50 % effective dose) values below 10 μM. Berberine, emetine, and quinidine were the most active compounds found; their ED50 values and minimum inhibitory concentrations were comparable to those of the antitrypanosomal drugs suramin and diminazene aceturate. However, most of these compounds were also cytotoxic. In the case of emetine, the ratio of cytotoxic/trypanocidal activity was only 3 while for quinidine it was 300 indicating that this alkaloid could be a candidate for further drug development. DNA intercalation in combination with protein biosynthesis inhibition, which is the major mode of action of the active alkaloids, could be responsible for the observed trypanocidal and cytotoxic effects.

Key words

Alkaloids - African trypanosomes - HL-60 cells - antitrypanosomal activity - DNA intercalation - inhibition of protein biosynthesis

References

  • 1 Molyneux D H. Current public health status of trypanosomiases and leishmaniases. In: Hide G, Mottram JC, Coombs GH, Holmes PH, editors Trypanosomiasis and leishmaniasis: biology and control. CAB International Wallingford, Oxon; 1997: 39-50
    Search in Google Scholar
  • 2 Kristjanson P M, Swallow B M, Rowlands G J, Kruska R L, de Leeuw P N. Measuring the costs of African animal trypanosomiasis, the potential benefits of control and returns to research.  Agricultural Systems. 1999;  59 79-98
    CrossrefPubMedSearch in Google Scholar
  • 3 Croft S L. The current status of antiparasitic chemotherapy.  Parasitology. 1997 (Supplement);  114 3-15
    PubMedSearch in Google Scholar
  • 4 Ross C A, Sutherland D V. Drug resistance in trypanosomatids. In : Hide G, Mottram JC, Coombs GH, Holmes PH, editors Trypanosomiasis and leishmaniasis: biology and control. CAB International Wallingford, Oxon; 1997: 259-69
    Search in Google Scholar
  • 5 Wink M. Chemical ecology of alkaloids. In: Roberts MF, Wink M, editors Alkaloids: biochemistry, ecology and medicinal applications. Plenum New York; 1998: 265-300
    Search in Google Scholar
  • 6 Wink M, Schimmer O. Modes of action of defensive secondary metabolites. In: Wink M, editor Function of plant secondary metabolites and their exploitation in biotechnology. Annual Plant Reviews Vol. 3 Sheffield Acadamic Press and CRC Press Sheffield; 1999: 17-133
    Search in Google Scholar
  • 7 Wink M. Allelochemical properties and the raison d’être of alkaloids. In: Cordell G, editor The alkaloids. Vol. 43 Academic Press San Diego; 1993: 1-118
    Search in Google Scholar
  • 8 Wink M. Interference of alkoloids with neuroreceptors and ion channels. In: Atta-Ur-Rahman, editor Studies in natural products chemistry. Vol. 21 (B) Elsevier Amsterdam; 2000: 3-122
    Search in Google Scholar
  • 9 Wink M, Schmeller T, Latz-Brüning B. Modes of action of allelochemical alkaloids: interaction with neuroreceptors, DNA and other molecular targets.  Journal of Chemical Ecology. 1998;  24 1881-937
    CrossrefPubMedSearch in Google Scholar
  • 10 Hirumi H, Hirumi K, Doyle J J, Cross G AM. In vitro cloning of animal-infective bloodstream forms of Trypanosoma brucei .  Parasitology. 1980;  80 371-82
    PubMedSearch in Google Scholar
  • 11 Obexer W, Schmid C, Brun R. A novel in vitro screening assay for trypanocidal activity using the fluorescent dye BCECF-AM.  Tropical Medicine and Parasitology. 1995;  46 45-8
    PubMedSearch in Google Scholar
  • 12 Baltz T, Baltz D, Giroud C h, Crockett J. Cultivation in a semi-defined medium of animal infective forms of Trypanosoma brucei, T. equiperdum, T. evansi, T. rhodesiense and T. gambiense .  EMBO Journal. 1985;  4 1273-7
    PubMedSearch in Google Scholar
  • 13 Räz B, Iten M, Grether-Bühler Y, Kaminsky R, Brun R. The Alamar Blue® assay to determine drug sensitivity of African trypanosomes (T. b. rhodesiense and T. b. gambiense) in vitro .  Acta Tropica. 1997;  68 139-47
    CrossrefPubMedSearch in Google Scholar
  • 14 Scory S, Steverding D. Differential toxicity of ricin and diphtheria toxin for bloodstream forms of Trypanosoma brucei .  Molecular and Biochemical Parasitology. 1997;  90 289-95
    CrossrefPubMedSearch in Google Scholar
  • 15 Huber W, Koella J C. A comparison of three methods of estimating EC50 in studies of drug resistance of malaria parasites.  Acta Tropica. 1993;  55 257-61
    CrossrefPubMedSearch in Google Scholar
  • 16 Brun R, Baeriswyl S, Kunz C. In vitro drug sensitivity of Trypanosoma gambiense isolates.  Acta Tropica. 1989;  46 369-76
    CrossrefPubMedSearch in Google Scholar
  • 17 Freiburghaus F, Kaminsky R, Nkunya M HH, Brun R. Evaluation of African medicinal plants for their in vitro trypanocidal activity.  Journal of Ethnopharmacology. 1996;  55 1-11
    CrossrefPubMedSearch in Google Scholar
  • 18 Williamson J, Scott-Finnigan T J. Trypanocidal activity of antitumor antibiotics and other metabolic inhibitors.  Antimicrobial Agents and Chemotherapy. 1978;  13 735-44
    PubMedSearch in Google Scholar
  • 19 Fournet A, Ferreira M E, Rojas de Arias A, Schinini A, Nakayama H, Torres S. et al . The effect of bisbenzylisoquinoline alkaloids on Trypanosoma cruzi infections in mice.  International Journal of Antimicrobial Agents. 1997;  8 163-70
    CrossrefPubMedSearch in Google Scholar
  • 20 Rivas P, Cassels B K, Morello A, Repetto Y. Effects of some β-carboline alkaloids on intact Trypanosoma cruzi epimastigotes. Comparative Biochemistry and Physiology.  Part C, Pharmacology, Toxicology and Endocrinology. 1999;  122 27-31
    PubMedSearch in Google Scholar
  • 21 Chataing B, Concepcion J L, Lobaton R, Usubillaga A. Inhibition of Trypanosoma cruzi growth in vitro by Solanum alkaloids: a comparison with ketoconazole.  Planta Medica. 1998;  64 31-6
    PubMedSearch in Google Scholar
  • 22 Waechter A L, Cavé A, Hocquemiller R, Bories C, Muñoz V, Fournet A. Antiprotozoal activity of aporphine alkaloids isolated from Unonopsis buchtienii (Annonaceae).  Phytotherapy Research. 1999;  13 175-7
    CrossrefPubMedSearch in Google Scholar
  • 23 Schmeller T, Sauerwein M, Sporer F, Wink M, Müller W E. Binding of quinolizidine alkaloids to nicotinic and muscarinic receptors.  Journal of Natural Products. 1994;  57 1316-9
    CrossrefPubMedSearch in Google Scholar
  • 24 Schmeller T, Sporer F, Sauerwein M, Wink M. Binding of tropane alkaloids to nicotinic and muscarinic receptors.  Pharmazie. 1995;  50 493-5
    PubMedSearch in Google Scholar
  • 25 Schmeller T, El-Shazly A, Wink M. Allelochemical activities of pyrrolizidine alkaloids: interactions with neuroreceptors and acetylcholine related enzymes.  Journal of Chemical Ecology. 1997;  23 399-416
    CrossrefPubMedSearch in Google Scholar

Prof. Dr. Michael Wink

Institut für Pharmazeutische Biologie

Universität Heidelberg

Im Neuenheimer Feld 364

69120 Heidelberg

Germany

Email: Wink@urz.uni-heidelberg.de

Fax: 0049-6221-544884