Abstract
A series of novel artemisinin derivatives were synthesized from artemisinin and different anilines. All compounds were obtained as β-isomers. The target compounds were evaluated for inhibition activity against Plasmodium falciparum falcipain-2 in vitro, and most of them exhibited potent inhibition in the low micromolar range and proved to be new types of falcipain-2 inhibitors.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Begue, J. P. and Bonnet, D. D., The future of antimalarials: artemisins and synthetic endoperoxides. Drugs Future, 30, 509–518 (2005).
Brossi, A., Venugopalan, B., Dominguez, G. L., Yeh, H. J. C., Flippen, A. J. L., Buchs, P., Luo, X.-D., Milhous, W., and Peters, W., Arteether, a new antimalarial drug: synthesis and antimalarial properties. J. Med. Chem., 31, 645–650 (1988).
Cerecetto, H., Maio, R. D., Gonzalez, M., Risso, M., Sagrera, G., Seoane, G., Denicola, A., Peluffo, G., Quijano, C., Stoppani, A. O. M., Paulino, M., Olea, A. C., and Basombrio, M. A., Synthesis and antitrypanosomal evaluation of E-isomers of 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives. structure-activity relationships. Eur. J. Med. Chem., 35, 343–350 (2000).
Chipeleme, A., Gut, J., Rosenthal, P. J., and Chibale, K., Synthesis and biological evaluation of phenolic Mannich bases of benzaldehyde and (thio)semicarbazone derivatives against the cystein protease falcipain-2 and a chloroquine resistant strain of Plasmodium falciparum. Bioorg. Med. Chem., 15, 273–282 (2007).
Dimri, A. K. and Parmar, S. S., Synthesis of 3-aryl-4-oxothiazolin-2-yl-(4-ethoxy-3-methoxy)phenyl hydrazones as possible anticonvulsants. J. Heterocycl. Chem., 15, 335–336 (1978).
Ettari, R., Bova, F., Zappala, M., Grasso, S., and Micale, N., Falcipain-2 inhibitors. Med. Res. Rev., 30, 136–137 (2010).
Klayman, D. L., Bartosevich, J. F., Griffin, T. S., Mason, C. J., and Scovill, J. P., 2-Acetylpyridine thiosemicarbazones. 1. a new class of potential antimalarial agents. J. Med. Chem., 22, 855–862 (1979).
Klayman, D. L., Qinghaosu (artemisinin): an antimalarial drug from China. Science, 228, 1049–1055 (1985).
Li, H., Huang, J., Chen, L., Liu, X., Chen, T., Zhu, J., Lu, W., Shen, X., Li, J., Hilgenfeld, R., and Jiang, H., Identification of novel falcipain-2 inhibitors as potential antimalarial agents through structure-based virtual screening. J. Med. Chem., 52, 4936–4940 (2009).
Liang, J. and Li, Y., Synthesis of the aryl ether derivatives of artemisinin. Chin. J. Med. Chem., 6, 22–25 (1996).
Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K., and Olson, A. J., Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem., 19, 1639–1662 (1998).
Muraleedharan, K. M. and Mitchell, A. A., Progress in the development of peroxide-based anti-parasitic agents. Drug Discov. Today, 14, 793–803 (2009).
O’Neil, P. M., Miller, A., Bishop, L. P. D., Hindley, S., Maggs, J. L., Ward, S. A., Roberts, S. M., Scheinmann, F., Stachulski, A. K., Posner, G. H., and Park, B. K., Synthesis, antimalarial activity, biomimetic iron(II) chemistry, and in vivo metabolism of novel, potent C-10-phenoxy derivatives of dihydroartemisinin. J. Med. Chem., 44, 58–68 (2001).
Rosenthal, P. J., Sijwali, P. S., Singh, A., and Shenai, B. R., Cysteine proteases of malaria parasites: Targets for chemotherapy. Curr. Pharm. Des., 8, 1659–1672 (2002).
Shenai, B. R., Sijwali, P. S., Singh, A., and Rosenthal, P. J., Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of plasmodium falciparum. J. Biol. Chem., 275, 29000–29010 (2000).
Walcourt, A., Loyevsky, M., Lovejoy, D. B., Gordeuk, V. R., and Richardson, D. R., Novel aroylhydrazone and thiosemicarbazone iron chelators with anti-malarial activity against chloroquine-resistant and -sensitive parasites. Int. J. Biochem. Cell Biol., 36, 401–407 (2004).
World Health Organization (WHO), World malarial report 2010. WHO, Geneva, http://www.who.int/malaria/world_malaria_report_2010/worldmalariareport2010.pdf (2010).
Yang, Z.-S., Zhou, W.-L., Sui, Y., Wang, J.-X., Wu, J.-M., Zhou, Y., Zhang, Y., He, P.-L., Han, J.-Y., Tang, W., Li, Y., and Zuo, J.-P., Synthesis and immunosuppressive activity of new artemisinin derivatives. Part I. [12(β or α)-dihydroartemisininoxy] phen(ox)yl aliphatic acids/esters. J. Med. Chem., 48, 4608–4617 (2005).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Liu, Y., Lu, WQ., Cui, KQ. et al. Synthesis and biological activities of novel artemisinin derivatives as cysteine protease falcipain-2 inhibitors. Arch. Pharm. Res. 35, 1525–1531 (2012). https://doi.org/10.1007/s12272-012-0902-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-012-0902-4