Hostname: page-component-cd9895bd7-hc48f Total loading time: 0 Render date: 2024-12-23T12:28:09.040Z Has data issue: false hasContentIssue false
  • English
  • Français

Blood schizontocidal activity of selected 1,2,4-trioxanes (Fenozans) against the multidrug-resistant strain of Plasmodium yoelii nigeriensis (MDR) in vivo

Published online by Cambridge University Press:  09 June 2006

R. TRIPATHI ,
C. W. JEFFORD  and
G. P. DUTTA
R. TRIPATHI
Affiliation:
Division of Parasitology, Central Drug Research Institute, Lucknow, India
C. W. JEFFORD
Affiliation:
Department of Organic Chemistry, University of Geneva, CH-12, Geneva, Switzerland
Get access Rights & Permissions [Opens in a new window]

Abstract

Blood schizontocidal activity of 10 selected cis-fused cyclopenteno-1,2,4-trioxanes (namely Fenozan compound nos 6, 7, 11, 27, 32, 39, 44, 45, 48 and 51) have been re-investigated to establish their curative doses against the multidrug-resistant Plasmodium yoelii nigeriensis strain, which is lethal in Swiss mice. Freshly prepared formulations of these compounds prepared either in neutral groundnut (peanut) oil or in dimethyl sulfoxide (DMSO)-Tween-water, were compared for their antimalarial activity. Only 2 compounds, namely Fenozan derivatives 11 and 45, formulated in neutral groundnut oil for oral administration, showed highest activity with 100% cure rate in MDR P. yoelii nigeriensis-infected mice, while the DMSO-Tween-water formulations were inactive. Fenozan-48 produced 72·2% cure, when administered orally in groundnut oil (formulation) while its DMSO-Tween formulation was inactive. In the case of Fenozan 7, the oil and DMSO-Tween formulations produced 92·3 and 76·0% cures respectively. Fenozan derivatives nos 6, 27, 32, 39, 44 and 51 were not protective either in groundnut oil or DMSO-Tween oral formulations. The present study has applied more rigorous criteria for selection of active compounds, and has identified the 3,3-spirocyclopentane derivative Fenozan 11, and the 3,3-spirohydropyran derivative Fenozan 45, as potential blood schizontocides which can completely eliminate multidrug-resistant malaria infection in mice. Both these compounds are candidates for pre-clinical development. The present study advocates the preferred use of an oil vehicle for oral evaluation of potential antimalarial trioxanes/fenozans instead of the DMSO formulation, which gives inferior curative efficacy.

Keywords

trioxanesfenozansantimalarialsPlasmodium yoelii nigeriensismultidrug resistant (MDR)
Type
Research Article
Information
Parasitology , Volume 133 , Issue 1 , July 2006 , pp. 1 - 9
Copyright
2006 Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Anon ( 1982 a). China Cooperative Research Group on Qinghaosu and its derivative antimalarials: the chemistry and synthesis of qinghaosu derivatives. Journal of Traditional Chinese Medicine 2, 9–16.
Anon ( 1982 b). China Cooperative Research Group on Qinghaosu and its derivatives as antimalarials: antimalarial efficacy and mode of action of qinghaosu and its derivatives in experimental models. Journal of Traditional Chinese Medicine 2, 17–24.
Anon ( 2001). The artemether-quinine metaanalysis study group. A metaanalysis using individual patient data of trials comprising artemether with quinine in the treatment of severe falciparum malaria. Transactions of the Royal Society Tropical Medicine and Hygiene 95, 637–650.
Awad, M. I., Alkadru, A. M. Y., Behrens, R. H., Baraka, Q. Z. and Eltayeb, I. B. ( 2003). Descriptive study on the efficacy and safety of artesunate suppository in combination with other antimalarials in the treatment of severe malaria in Sudan. American Journal of Tropical Medicine and Hygiene 68, 153–158.Google Scholar
Dutta, G. P. and Tripathi, R. ( 1996). Arteether α/β – a fast acting antimalarial. Japanese Journal of Tropical Medicine and Hygiene 24, 65–69.Google Scholar
Dutta, G. P. and Tripathi, R. ( 2003). New antimalarial drug development in India: α/β Arteether. Proceedings of the Indian National Science Academy 69B, 861–870.Google Scholar
Jefford, C. W., McGoran, E. C., Boukouvalas, J., Richardson, G., Robinson, B. L. and Peters, W. ( 1988). Synthesis of new 1,2,4-trioxanes and their antimalarial activity. Helvetica Chimica Acta 71, 1805–1812.CrossRefGoogle Scholar
Jefford, C. W., Velarde, J. A., Bernardinelli, G., Bray, D. H., Warhurst, D. C. and Milhous, W. K. ( 1993). Synthesis, structure and antimalarial activity of Tricyclic 1,2,4-trioxanes related to artemisinin. Helvetica Chimica Acta 76, 2775–2778.CrossRefGoogle Scholar
Jefford, C. W., Shigeo Kohmoto, S., Jaggi, D., Timari, G., Rossier, J. C., Rudaz, M., Barbuzzi, O., Gerard, D., Burger, U., Kamlaprija, P., Mareda, J., Bernardinelli, G., Manzanares, I., Canfield, C. J., Fleck, S. L., Robinson, B. L. and Peters, W. ( 1995). Synthesis, structure and antimalarial activity of some enantiomerically pure, cis-fused cyclopenteno 1,2,4-trioxanes. Helvetica Chimica Acta 78, 647–662.CrossRefGoogle Scholar
Jerrold, H. Z. ( 1974). Biostastical Analysis. Prentice-Hall, Inc, New Jersey, USA.
Meshnick, S. R., Jefford, C. W., Posner, G. H., Avery, M. A. and Peter, W. ( 1996). Second-generation antimalarial endoperoxides. Parasitology Today 12, 79–82.CrossRefGoogle Scholar
Mishra, S. K., Asthana, O. P., Mohanty, S., Srivastava, J. S., Satpathy, S. K., Satpathy, S., Patnaik, J. K., Rath, P. K. and Varghese, K. ( 1995). Effectiveness of α/β-arteether in acute falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 89, 299–301.CrossRefGoogle Scholar
Olliaro, P., Cattani, J. and Wirth, D. ( 1996). Malaria, the submerged disease. Journal of the American Medical Association 275, 230–233.CrossRefGoogle Scholar
O'Neill, P. M. ( 2004). A worthy adversary for malaria. Nature, London 430, 838–839.CrossRefGoogle Scholar
Peters, W. ( 1975). The chemotherapy of rodent malaria, XXII. The value of drug-resistant strains of P. berghei in screening for blood schizontocidal activity. Annals of Tropical Medicine and Parasitology 69, 155–177.CrossRefGoogle Scholar
Peters, W. ( 1998) Antimalarial drugs. U.S. Patent no.5, 834, 505.
Peters, W., Fleck, S. L., Robinson, B. L., Stewart, L. B. and Jefford, C. W. ( 2002). The chemotherapy of rodent malaria. LX. The importance of formulation in evaluating the blood schizontocidal activity of some endoperoxide antimalarials. Annals of Tropical Medicine and Parasitology 96, 559–573.Google Scholar
Peters, W., Robinson, B. L., Rossier, J. C. and Jefford, C. W. ( 1993 a). The chemotherapy of rodent malaria XLVIII. The activities of some synthetic 1,2,4-trioxanes against chloroquine sensitive and chlorqouine resistant parasites. Part-I Studies leading to the development of novel cis-fused cyclopenteno derivatives. Annals of Tropical Medicine and Parasitology 87, 1–7.Google Scholar
Peters, W., Robinson, B. L., Rossier, J. C., Misra, D., Jefford, C. W. and Rossiter, J. C. ( 1993 b). The chemotherapy of rodent malaria XLIX. The activities of some synthetic 1,2,4-trioxanes against chloroquine sensitive and chloroquine resistant parasites Part 2. Structure activity studies on cis-fused cyclopenteno-1,2,4-trioxanes (fenozans) against drug sensitive and drug resistant lines of Plasmodium berghei and P. yoelii spp. NS in vivo. Annals of Tropical Medicine and Parasitology 87, 9–16.Google Scholar
Peters, W., Robinson, B. L., Tovey, G., Rossier, J. C. and Jefford, C. W. ( 1993 c). The chemotherapy of rodent malaria. The activities of some synthetic 1,2,4-trioxanes against chloroquine sensitive and chloroquine resistant parasites Part 3, Observation on ‘Fenozan 50F’ a difluorinated 3,3′-spirocyclopentane 1,2,4-trioxane. Annals of Tropical Medicine and Parasitology 87, 111–123.Google Scholar
Posner, G. H., Oh, C. H., Webster, H. K., Ager, Jr., A. L. and Rossan, R. N. ( 1994). New antimalrial, tricyclic 1,2,4-trioxanes evaluations in mice and monkey. American Journal of Tropical Medicine and Hygiene 50, 522–526.CrossRefGoogle Scholar
Remme, J. H. F., Blas, E., Chitsulo, L., Desjeux, P. M. P., Engers, H. D., Kanyok, T. P., Kayondo, J. F. K., Kiloy, D. W., Kumaraswami, V., Lazolins, J. K., Nunn, P. P., Oduola, A., Ridley, R. G., Toure, Y. T., Zicker, F. and Marel, C. M. ( 2002). Strategic emphases for tropical diseases research: a TDR prospective. Trends in Parasitology 18, 421–426.CrossRefGoogle Scholar
Tripathi, R., Dhawan, S. and Dutta, G. P. ( 2005). Blood schizontocidal activity of azithromycin and its combination with α/β arteether against multi-drug resistant Plasmodium yoelii nigeriensis a novel MDR parasite model for antimalarial screening. Parasitology 131, 295–301.CrossRefGoogle Scholar
Vennerstrom, J. L., ArbeBarnes, S., Brun, R., Charman, S. A., Chiu, F. C., Chollet, J., Dong, Y., Dorn, A., Hunziker, D., Matile, H., McIntosh, K., Padmanilayam, M., SantoTomas, J., Scheurer, C., Scorneaux, B., Tang, Y., Urwyler, H., Wittlin, S. and Charman, W. N. ( 2004). Identification of an antimalarial synthetic trioxolane drug development candidate. Nature, London 430, 900–904.CrossRefGoogle Scholar
Wellems, T. E. ( 1991). Molecular genetics of drug resistance in Plasmodium falciparum malaria. Parasitology Today 7, 110–112.CrossRefGoogle Scholar
WORLD HEALTH ORGANIZATION ( 2000). Implementation of collaborative activities on ‘Roll Back Malaria’ in the South-East Asia Region. World Health Organization, Regional Office for South-East Asia, New Delhi, June, pp. 1–24.
WHO NEWS ( 2003). Malaria kills 3000 children a day in Africa. Bulletin of the World Health Organization 81, 472.
Zaman, S. S. and Sharma, R. P. ( 1991). Some aspects of the chemistry and biological activity of artemisinin and related antimalarials. Heterocycles 32, 1593–1638.Google Scholar