In Vivo ANTIPLASMODIAL ACTIVITY AND MECHANISM OF ACTION OF 1,10-PHENANTHROLINE DERIVATIVES

Mustofa .; Ange Desire Yapi; Alexis Valentin

doi:10.14499/indonesianjpharm0iss0pp142-149

In Vivo ANTIPLASMODIAL ACTIVITY AND MECHANISM OF ACTION OF 1,10-PHENANTHROLINE DERIVATIVES

Mustofa ., Ange Desire Yapi, Alexis Valentin

Abstract

The rapidly increasing resistance of Plasmodium falciparum to the most commonly used antimalarial drug indicates the urgent need for new antimalarial compounds. Previous study showed that among thirteen derivatives of 1,10-phenanthroline, four compounds were active in vitro and potential for further development. The study was conducted to provide the in vivo antiplasmodial activity of four 1,10-phenanthroline derivatives and to evaluate the possibility of their mechanism of action. The in vivo antiplasmodial activity of the four compounds was evaluated by a standard 4-day test on Plasmodium venckei petteri infected mice. The study of haem polymerization inhibitory activity (HPIA) and the potentiating of those compounds in combination with halofantrine and inhibitor protease (E64) were carried out to evaluate its mechanism of actions. The results showed that among four compounds tested, compound 1 (2,10-methyl-3-(2-chloroethyl)-4-chloropirydo [2,3-i] quinolineium iodide) was the most active compound with DE50 was 0.22 ± 0.03 mg/kg BW. This molecule less active than halofantrine, but more active than chloroquine. The HPIA of 1,10-phenanthroline derivatives tested (IC50 HPIA was 1.57-1.95 mmol/well) did not vary significantly. These IC50 HPIA values were significantly lower than halofantrine (CI50 HPIA was 0.12 ± 0.04 mmol/well) and than chloroquine (CI50 HPIA was 0.75 ± 0.03 mmol/well). Combination the 1,10-phenanthroline derivatives and halofantrine produced simple additive effect that implies that each drug posses a different mechanism of action. Conversely, there was antagonist interaction between 1,10-phenanthroline derivatives and E64 showing that the drugs have a similar mechanism of action. It can be concluded that the compound 1 appears as a potential antimalarial compound. In addition, the possible mechanism of action of this compound is inhibitation of protease involved in haemoglobine degradation within the malaria parasite.

Key words : 1,10-phenanthroline – in vivo antiplasmodial – haem polymerization inhibitory
activity – protease inhibitor .

Full Text:

Untitled

References

Basilico, N., Pagani, E., Monti, D., Olliaro, P., Taramelli, D., 1998. A microtitre-based method for measuring the haem polymerization inhibitory (HPIA) of antimalarial drugs, J. Antimicrob. Chemother. 42, 55-66.

Desjardins, R.E., Canfield, C.J,, Haynes, J.D., Chulay, J.D., 1979. Quantitative assesment of antimalarial activity in vitro by semi-automated microdilution technique, Antimicrob. Agents Chemother. 16, 710-718.

Dorn, A., Vippaguta, S.R., Matile, H., Bubendorf, A., Ridley, R.G., 1998, A comparison and analysis of several ways to promote haematin (haem) polymerisation and an assesment of its initiation in vitro, Biochem. Pharmacol., 55, 737-747.

Gail, E.S., Havkicki, I., 1994. In vitro drug interaction between amantadine and classical antimalarial drugs in Plasmodium falciparum infections, Trans. R. Soc. Trop. Med. Hyg. 88, 683-686.

Gamboa de Dominguez, N.D., Rosenthal, P.J., 1996, Cysteine proteinase inhibitors block early steps in hemoglobin degradation by cultured malaria parasites, Blood, 87, 4448-4454.

Hawley, S.R., Bray, P.G., Mungthin, M., Atkinson, J.D., O’Neil, P.M., Ward, SA. Relationship between antimalarial drug activity, accumulation and inhibition of heme polymeration in Plasmodium falciparum in vitro, Antimicrob. Agents Chemother. 42 (3), 682-686.

Mungthin, M., Bray, P.G., Ridley, R.G., Ward, S.A., 1998, Central role of hemoglobin degradation in mechanisms of action of 4-aminoquinolines, quinoline methanols and phenanthrene methanols, Antimicrob. Agents Chemother., 42 (11), 2973-2977.

Mustofa, 2000. Activite in vitro et in vivo de divers antipaludiaues d’origine naturelle ou synthetiaue: effets potentialisateurs et modes d’action possibles, Universite Montpeliier I.

Peters, W., 1987. Chemotherapy and drugs resistance in malaria, Vol. 1, Academic Press, Inc., New York

Rosenthal, P.J., 1995, Plasmodium falciparum : effects of proteinase inhibitors on globin hydrolysis by cultured malaria parasites, Exp. Parasitol. 80, 272-281.

Sowunmi, A., Falade, C.O., Oduola, A.M., Agundahusi, O.A., Fehintola, F.A., Gbotosho, G.O., Larcier, P., Salako, L.A. 1998. Cardiac effects of halofantrine in children suffering from acute uncomplicated falciparum malaria, Trans. R. Soc. Trop. Med. Hyg., 92(4), 446-448.

Touze, J.E., Fourcade, L., Peyron, F., Heno, P., Deharo, J.C., 1997, Is halofantrine still advisible in malaria attacks? Ann. Trop. Med. Parasitol. 91(1), 867-873.

Touze, J.E., Peyron, F., Mojon, M., Fourcade, L., 1995, Halofantrine : for new rules of prescription, Presse Med. 24, (7), 366-369.

Vial, H., Ancelin, M.L., 1998, Recherches de nouvelles molecules antipaludiaues: une urgence and unespoir, Pathol. Biol., 42, 138-144.

Wallace, R.J., McKain, N., 1996, Influence of 1,10-fenanthroline and its analogues, other chelators and transtition metal ions on dipeptidase activity of rumen bacterium, Provotella ruminicoba. J. Appl. Bacteriol., 81 (1), 42-47.

Wallace, R.J., Newbold, C.J., McKain, N., 1996, Inhibition by 1,10-phenanthroline of the breakdown on peptidase by rumen bacteria and protozoa, J. Appl. Bacteriol., 80, 425-430.

Winter, R.W., Cornell, K.A., Johnson, L.L., Ignatushcenko, M., Hinrichs, D.J., Riscoe, M.K., 1996, Potentiation of the antimalarial agent rufigallo, Antimicrob. Agents Chemother. 40(6), 1408-1411.

World Health Organization, 1998, Roll back Malaria. A global partnership, WHO, Geneva.

Van Agmael, M., Bouchaud, O., Malvy, D., Delmont, J., Danis, M., Barrette, S., Gras, C., Bernard, J., Touze, J.E., Gathmann, I., Mull, R. 1999, The comparative efficacy and tolerability of CGP 56697 (artemether + lumefantrine) versus halofantrine in the treatment of uncomplicated falciparum malaria in travellers returning from the Tropic to The Netherlands and France, Int. J. Antimicrob. Agents. 12 (2), 159-169.

Yapi, A.D., Mustofa,, Valentin, A., Chavignon, O., Teulade, J.C., Mallie, M., Chapat, J.P., Blache, Y., 2000. New potential antimalarial agents : synthesis and biological activities of original diaza analogs phenanthrene, Chem. Pharm. Bull. 48 (12), 1886-1889.

Ye, Z., Dykel, K.V., Castranova, V., 1989. The potentiating action of tetrandine in combination with chloroquine or qinghaosu against chloroquine sensitive and resistant falciparum malaria, Biochem. Biophys. Re. Comm. 159 (1), 242-247.

DOI: http://dx.doi.org/10.14499/indonesianjpharm0iss0pp142-149