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

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
• 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
• 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
• 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
• 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
• 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
• 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
• 8 Bisset N G, Das B, Parello J. Alkaloids from the leaves of Strychnos icaja Baill.  Tetrahedron. 1973;  29 4137-48
• 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
• 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
• 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
• 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
• 13 Trager W, Jensen J B. Human malaria parasites in continuous culture.  Science. 1976;  193 673-5
• 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
• 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
• 16 Berenbaum M. What is synergy?.  Pharmacological Reviews. 1989;  41 93-141
• 17 Loewe S. The problem of synergism and antagonism of combined drugs.  Arzneimittelforschung. 1953;  3 285-90
• 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
• 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
• 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
• 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