Dipeptide Derivatives of Primaquine as Transmission-Blocking Antimalarials: Effect of Aliphatic Side-Chain Acylation on the Gametocytocidal Activity and on the Formation of Carboxyprimaquine in Rat Liver Homogenates
Purpose. Dipeptide derivatives of primaquine (PQ) with reduced oxidative deamination to the inactive metabolite carboxypnmaquine were synthesized and evaluated as a novel class of transmission-blocking antimalarials.
Methods. Antimalarial activity was studied using a model consisting of mefloquine-resistant Plasmodium berghei ANKA 25R/10, Balb C mice, and Anopheles stephensi mosquitoes. Metabolic studies were performed with rat liver homogenates, and the incubates were analyzed by HPLC.
Results. All dipeptide derivatives and glycyl-PQ completely inhibited the appearance of oocysts in the midguts of the mosquitoes at 15 mg/ kg, while N-acetylprimaquine was not active at this dose. However, none of the title compounds were able to block oocyst production at 3.75 mg/kg, in contrast with primaquine. Exception for sarc-gly-PQ, all remaining compounds prevented sporozoite formation in the salivary glands of mosquitoes at a dose of 3.75 mg/kg. Simultaneous hydrolysis to primaquine and gly-PQ ocurred with the following order of Vmax/ Km: for primaquine formation, L-ala-gly-PQ > L-phe-gly-PQ > gly-gly-PQ; and for gly-PQ formation, L-phe-gly-PQ > L-ala-gly-PQ > gly-gly-PQ. In contrast, primaquine was not released from D-phe-gly-PQ, sarc-gly-PQ, and N-acetylprimaquine. Neither carboxyprimaquine nor 8-amino- 6-methoxy- quinoline were detected in any of the incubation mixtures.
Conclusions. The title compounds prevent the development of the sporogonic cycle of Plasmodium berghei. Gametocytocidal activity is independent of the rate and pathway of primaquine formation. Acylation of the aliphatic side-chain effectively prevents the formation of Carboxyprimaquine, but the presence of a terminal amino group appears to be essential for the gametocytocidal activity.
Unable to display preview. Download preview PDF.
- 1.Practical Chemotherapy of Malaria. Technical Report Series 805. WHO, Geneva, 1990, pp. 7–17.Google Scholar
- 2.D. A. Warrell. Treatment and prevention of malaria. In H. M. Gilles and D. A. Warrell (eds.), Bruce-Chwatt's Essential Malariology, Edward-Arnold, 3th Ed., Sevenoaks, 1993, pp. 164–195.Google Scholar
- 3.P. F. Beales. The use of drugs for malaria control. In W. H. Wernsdofer and I. McGregor (eds.), Malaria, Principles and Practice of Malariology, Churchill Livingstone, New York, 1988, pp. 1263–1285.Google Scholar
- 4.K. H. Rieckmann, J. V. McNamara, H. Frischer, T. A. Stockert. P. E. Carson, and R. D. Powell. Gametocytocidal and sporontocidal effects of primaquine and of sulfadiazine with pyrimethamine in a chloroquine-resistant strain of Plasmodium falciparum. Bull. WHO 38:625–632 (1968).Google Scholar
- 5.W. Peters and B. L. Robinson. The activity of primaquine and its possible metabolites against rodent malaria. In W. H. Wernsdorfer and P. I. Trigg (Ed.), Primaquine: Pharmacokinetics, Metabolism, Toxicity and Activity; John Wiley, Chichester, 1984, pp. 93–101.Google Scholar
- 6.A. Brossi, P. Millet, I. Landau, M. E. Bembenek, and C. W. Abell. Antimalarial activity and inhibition of monoamino oxidases A and B by exo-erythrocytic antimalarials. FEBS Letters 214:291–294 (1987).Google Scholar
- 7.A. M. Clark, J. K. Baker, and J. D. McChesney. Excretion, distribution, and metabolism of primaquine in rats. J. Pharm. Sci. 73:502–506 (1984).Google Scholar
- 8.J. K. Baker, J. A. Bedford, A. M. Clark, and J. D. McChesney. Metabolism and distribution of primaquine in monkeys. Pharm. Res. 1:98–100 (1984).Google Scholar
- 9.G. W. Mihaly, S. A. Ward, G. Edwards, M. L'E Orme, and A. M. Breckenridge. Pharmacokinetics of primaquine: identification of the carboxylic acid derivative as a major plasma metabolite. Br. J. Clin. Pharmacol. 17:441–446 (1984).Google Scholar
- 10.J. K. Baker, R. H. Yarber, N. P. D. Nanayakkara, J. D. McChesney, F. Homo, and I. Landau. Effect of aliphatic side-chain substituents on the antimalarial activity and on the metabolism of primaquine studied using mitochondria and microsome preparations. Pharm. Res. 7:91–95 (1990).Google Scholar
- 11.A. Trouet, P. Pirson, R. Steiger, M. Masquelier, R. Baurain, and J. Gillet. Development of new derivatives of primaquine by association with lysosomotropic carriers. Bull. WHO 59:449–458 (1981).Google Scholar
- 12.A. Philip, J. A. Kepler, B. H. Johnson, and F. Y. Carroll. Peptide derivatives of primaquine as potential antimalarial agents. J. Med. Chem. 31:870–874 (1988).Google Scholar
- 13.R. Jain, S. Jain, R. C. Gupta, N. Anand, G. P. Dutta, and S. K. Puri. Synthesis of amino acid derivatives of 8-[(4-amino-1-butyl)amino]-6-methoxy-4-substituted]-4,5-disubstituted quinolines as potential antimalarial agents. Ind. J. Chem. 33B:251–254 (1994).Google Scholar
- 14.R. Borissova, P. Stjarnkvist, M. O. Karlsson, and I. Sjoholm. Biodegradable microspheres. 17. Lysosomal degradation of primaquine-peptide spacer arms. J. Pharm. Sci. 84:256–262 (1995).Google Scholar
- 15.R. B. Silverman. Radical ideas about monoamine oxidase. Acc. Chem. Res. 28:335–342 (1995)Google Scholar
- 16.J. Iley and L. Constantino. The microsomal dealkylation of N,N-dialkylbenzamides. Biochem. Pharmacol. 47:275–280 (1994).Google Scholar
- 17.S. Abu-El-Hay, R. Allahyari, E. Chavez, I. M. Frazer, and A. Strother. Effects of an NADPH-generating system on primaquine degradation by hamster liver fractions. Xenobiotica 18:1165–1178 (1988).Google Scholar
- 18.J. K. McDonald and C. Schwarbe. Intracelular exopeptidases. In A. J. Barrett (ed.), Proteinases in Mammalian Cells and Tissues, North-Holland, Amsterdam, 1979, pp 311–391.Google Scholar
- 19.R. E. Coleman, J. A. Vaughan, D. O. Hayes, M. R. Hollingdale, and V. E. Do Rosário. Effect of mefloquine and artemisinin on the sporogonic cycle of Plasmodium berghei ANKA in Anopheles stephensi mosquitoes. Acta Leidensia 57:61–74 (1988).Google Scholar
- 20.R. E. Coleman, A. M. Clavin, and W. K. Milhous. Gametocytocidal and sporontocidal activity of antimalarials against Plasmodium berghei ANKA in ICR mice and Anopheles stephensi mosquitoes. Am. J. Tropic. Med. Hyg. 46:169–182 (1992).Google Scholar
- 21.R. E. Coleman, A. K. Nath, I. Schneider, G.-H. Song, T. A. Klein, and W. K. Milhous. Prevention of sporogony of Plasmodium falciparum and P. berghei in Anopheles stephensi mosquitoes by transmission-blocking antimalarials. Am. J. Tropic. Med. Hyg. 50:646–653 (1994).Google Scholar
- 22.J. A. Vaughan, B. H. Noden and J. C. Beier. Population dynamics of Plasmodium falciparum sporogony in laboratory-infected Anopheles gambiae. J. Parasitol. 78:716–724 (1992).Google Scholar
- 23.F. P. Guengerich and T. L. Macdonald. Chemical mechanisms of catalysis by cytochromes P450: A unified view. Acc. Chem. Res. 17:9–16 (1984).Google Scholar
- 24.L. H. Schimdt. Relationships between chemical structures of 8-aminoquinolines and their capacities for radical cure of infections with plasmodium cynomolgi in Rhesus monkeys. Antimicrob. Agents Chemother. 24:615–652 (1983).Google Scholar
- 25.E. A. Nodiff, S. Chatterjee, and H. A. Musallam. Antimalarial activity of 8-aminoquinolines. Prog. Med. Chem. 28:1–40 (1991).Google Scholar