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Planta Med 2001; 67(6): 523-527
DOI: 10.1055/s-2001-16476
Original Paper
Pharmacology
© Georg Thieme Verlag Stuttgart · New York

Reversal of Chloroquine and Mefloquine Resistance in Plasmodium falciparum by the Two Monoindole Alkaloids, Icajine and Isoretuline

Michel Frédérich1, 2,*, Marie-Pierre Hayette2 , Monique Tits1 , Patrick De Mol2 , Luc Angenot1
  • 1 Laboratoire de Pharmacognosie, Institut de Pharmacie, Université de Liège, Belgium
  • 2 Laboratoire de Microbiologie Médicale, Institut de Pathologie, Université de Liège, Belgium
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Publikationsverlauf

August 18, 2000

December 2, 2000

Publikationsdatum:
17. August 2001 (online)

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Abstract

Eight naturally occurring monoindole alkaloids were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance of a chloroquine-resistant strain of Plasmodium falciparum. None of these indole alkaloids has significant intrinsic antiplasmodial activity (IC50 > 10 μM or 5 μg/ml). Nevertheless, three alkaloids (icajine, isoretuline and strychnobrasiline) did reverse chloroquine resistance at concentrations between 2.5 and 25 μg/ml (IF of 12.82 for isoretuline on W2 strain). The Interaction Factor (IF) equals 2, < 2, or > 2 for additive, antagonistic or synergistic effects of alkaloids on chloroquine inhibition, respectively. Icajine and isoretuline were also assessed in vitro for their mefloquine potentiating activity on a mefloquine-resistant strain of Plasmodium falciparum. Only icajine proved to be synergistic with mefloquine (IF = 15.38).

Key words

Plasmodium falciparum - chloroquine - mefloquine - indole alkaloid

References

  • 1 Martin S K, Oduola A M, Milhous W K. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil.  Science. 1987;  235 899-901
    PubMedSuche in Google Scholar
  • 2 Rasoanaivo P, Ratsimamanga-Urverg S, Milijaona R, Rafatro H, Rakoto-Ratsimamanga A, Galeffi C, Nicoletti M. In vitro and in vivo chloroquine-potentiating action of Strychnos myrtoides alkaloids against chloroquine-resistant strains of Plasmodium malaria.  Planta Medica. 1994;  60 13-6
    PubMedSuche in Google Scholar
  • 3 Frédérich M, Hayette M P, Tits M, De Mol P, Angenot L. In vitro activities of Strychnos alkaloids and extracts against Plasmodium falciparum .  Antimicrobial Agents and Chemotherapy. 1999;  43 2328-31
    PubMedSuche in Google Scholar
  • 4 Frédérich M, Tits M, Hayette M P, Brandt V, Penelle J, De Mol P, Llabres G, Angenot L. 10’-Hydroxyusambarensine, a new antimalarial bisindole alkaloid from the roots of Strychnos usambarensis .  Journal of Natural Products. 1999;  62 619-21
    CrossrefPubMedSuche in Google Scholar
  • 5 Frédérich M, De Pauw-Gillet M C, Llabres G, Tits M, Hayette M P, Brandt V, Penelle J, De Mol P, Angenot L. New antimalarial and cytotoxic sungucine derivatives from Strychnos icaja roots.  Planta Medica. 2000;  66 262-9
    Thieme ConnectPubMedSuche in Google Scholar
  • 6 Angenot L, Tits M. Isolement d’un nouvel alcaloïde et d’un triterpénoïde à partir du Strychnos henningsii du Zaïre.  Planta Medica.. 1981;  41 240-3
    PubMedSuche in Google Scholar
  • 7 Angenot L, Belem-Pinheiro M L, Imbiriba da Rocha A F, Poukens-Renwart P, Quetin-Leclercq J, Warin R. An indolinic cryptoalkaloid from Strychnos mattogrossensis .  Phytochemistry. 1990;  29 2746-9
    CrossrefPubMedSuche in Google Scholar
  • 8 Bisset N G, Das B, Parello J. Alkaloids from the leaves of Strychnos icaja Baill.  Tetrahedron. 1973;  29 4137-48
    CrossrefPubMedSuche in Google Scholar
  • 9 Brandt V, Tits M, Geerlings A, Frédérich M, Penelle J, Delaude C, Verpoorte R, Angenot L. Beta-carboline glucoalkaloids from Strychnos mellodora .  Phytochemistry. 1999;  51 1171-6
    CrossrefPubMedSuche in Google Scholar
  • 10 Tavernier D, Anteunis M JO, Tits M, Angenot L. The 1H NMR spectra of the Strychnos alkaloids retuline, isoretuline and their N-deacetyl compounds.  Bulletin de la Société Chimique Belge. 1978;  87 595-607
    PubMedSuche in Google Scholar
  • 11 Frédérich M, Tits M, Angenot L. Qualitative and quantitative evaluation of bisindole usambarane alkaloids in Strychnos usambarensis roots by high performance liquid chromatography-diode-array.  Phytochemical Analysis. 1998;  9 63-6
    CrossrefPubMedSuche in Google Scholar
  • 12 Gadi-Biala R, Tits M, Wauters J N, Angenot L. A new HPLC method for the assay of alkaloids in Strychnos nux-vomica and Strychnos ignatii .  Fitoterapia. 1996;  67 163-5
    PubMedSuche in Google Scholar
  • 13 Trager W, Jensen J B. Human malaria parasites in continuous culture.  Science. 1976;  193 673-5
    CrossrefPubMedSuche in Google Scholar
  • 14 Desjardins R E, Canfield C J, Haynes J D, Chulay J D. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique.  Antimicrobial Agents and Chemotherapy. 1979;  16 710-8
    PubMedSuche in Google Scholar
  • 15 Mirovsky P, Gay F, Bustos D, Mazier D, Gentilini M. Cloning of a fresh isolate of Plasmodium falciparum and drug sensitivity of the clones.  Transactions of the Royal Society of Tropical Medicine and Hygiene. 1990;  84 511-5
    CrossrefPubMedSuche in Google Scholar
  • 16 Berenbaum M. What is synergy?.  Pharmacological Reviews. 1989;  41 93-141
    PubMedSuche in Google Scholar
  • 17 Loewe S. The problem of synergism and antagonism of combined drugs.  Arzneimittelforschung. 1953;  3 285-90
    PubMedSuche in Google Scholar
  • 18 Frappier F, Jossang A, Soudon J, Calvo F, Rasoanaivo P, Ratsimamanga-Urveg S ,. et al . Bisbenzylisoquinolines as modulators of chloroquine resistance in Plasmodium falciparum and multidrug resistance in tumor cells.  Antimicrobial Agents and Chemotherapy. 1996;  40 1476-81
    PubMedSuche in Google Scholar
  • 19 Bonjean K A, De Pauw-Gillet M C, Quetin-Leclercq J, Angenot L, Bassleer R J. In vitro cytotoxic activity of two potential anticancer drugs isolated from Strychnos: strychnopentamine and usambarensine.  Anticancer Research. 1996;  16 1129-37
    PubMedSuche in Google Scholar
  • 20 Peters W, Robinson B L. The chemotherapy of rodent malaria. XLVI. Reversal of mefloquine resistance in rodent Plasmodium .  Annals of Tropical Medicine and Parasitology. 1991;  85 5-10
    PubMedSuche in Google Scholar
  • 21 Oduola A M, Omitowoju G O, Gerena L, Kyle D E, Milhous W K, Sowunmi A, Salako L A. Reversal of mefloquine resistance with penfluridol in isolates of Plasmodium falciparum from south-west Nigeria.  Transactions of the Royal Society of Tropical Medicine and Hygiene. 1993;  87 81-3
    CrossrefPubMedSuche in Google Scholar

Michel Frédérich

Laboratoire de Pharmacognosie

Institut de Pharmacie

Université de Liège

Avenue de l’hôpital 1

CHU du Sart Tilman, B36, tour 4

4000 Liège

Belgium

eMail: M.Frederich@ulg.ac.be

Fax: +32 4 366 43 32