Hostname: page-component-76fb5796d-wq484 Total loading time: 0 Render date: 2024-04-25T07:25:46.966Z Has data issue: false hasContentIssue false
  • English
  • Français

Chloroquine-containing organoruthenium complexes are fast-acting multistage antimalarial agents

Published online by Cambridge University Press:  21 July 2016

TAÍS S. MACEDO ,
LEGNA COLINA-VEGAS ,
MARCELO DA PAIXÃO ,
MARIBEL NAVARRO ,
BRENO C. BARRETO ,
POLIANA C. M. OLIVEIRA ,
SIMONE G. MACAMBIRA ,
MARTA MACHADO ,
MIGUEL PRUDÊNCIO  and
SARAH D'ALESSANDRO
...Show all authors
TAÍS S. MACEDO
Affiliation:
FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, 40296-710, Salvador, BA, Brazil
LEGNA COLINA-VEGAS
Affiliation:
Departamento de Química, UFSCAR, 13565-905, São Carlos, SP, Brazil
MARCELO DA PAIXÃO
Affiliation:
FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, 40296-710, Salvador, BA, Brazil
MARIBEL NAVARRO
Affiliation:
INMETRO, Xerém, 25250-020, Rio de Janeiro, RJ, Brazil
BRENO C. BARRETO
Affiliation:
FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, 40296-710, Salvador, BA, Brazil Instituto de Ciências da Saúde, Universidade Federal da Bahia, CEP 40110-100, Salvador, BA, Brazil
POLIANA C. M. OLIVEIRA
Affiliation:
FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, 40296-710, Salvador, BA, Brazil Instituto de Ciências da Saúde, Universidade Federal da Bahia, CEP 40110-100, Salvador, BA, Brazil
SIMONE G. MACAMBIRA
Affiliation:
Instituto de Ciências da Saúde, Universidade Federal da Bahia, CEP 40110-100, Salvador, BA, Brazil Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, CEP 41253-190 Salvador, BA, Brazil
MARTA MACHADO
Affiliation:
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
MIGUEL PRUDÊNCIO
Affiliation:
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
SARAH D'ALESSANDRO
Affiliation:
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy
NICOLETTA BASILICO
Affiliation:
Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Universitá degli Studi di Milano, 20133 Milan, Italy
DIOGO R. M. MOREIRA
Affiliation:
FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, 40296-710, Salvador, BA, Brazil
ALZIR A. BATISTA
Affiliation:
Departamento de Química, UFSCAR, 13565-905, São Carlos, SP, Brazil
MILENA B. P. SOARES*
Affiliation:
FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, 40296-710, Salvador, BA, Brazil Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, CEP 41253-190 Salvador, BA, Brazil
*
*Corresponding author: FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, CEP 40296-710, Salvador, BA, Brazil. Phone: (+55)71-31762292. E-mail: milena@bahia.fiocruz.br
Get access Rights & Permissions [Opens in a new window]

Summary

We report the pharmacological activity of organoruthenium complexes containing chloroquine (CQ) as a chelating ligand. The complexes displayed intraerythrocytic activity against CQ-sensitive 3D7 and CQ-resistant W2 strains of Plasmodium falciparum, with potency and selectivity indexes similar to those of CQ. Complexes displayed activity against all intraerythrocytic stages, but moderate activity against Plasmodium berghei liver stages. However, unlike CQ, organoruthenium complexes impaired gametocyte viability and exhibited fast parasiticidal activity against trophozoites for P. falciparum. This functional property results from the ability of complexes to quickly induce oxidative stress. The parasitaemia of P. berghei-infected mice was reduced by treatment with the complex. Our findings demonstrated that using chloroquine for the synthesis of organoruthenium complexes retains potency and selectivity while leading to an increase in the spectrum of action and parasite killing rate relative to CQ.

Keywords

MalariaPlasmodium falciparumPlasmodium bergheichloroquineorganoruthenium complexesoxidative stress
Type
Research Article
Information
Parasitology , Volume 143 , Issue 12 , October 2016 , pp. 1543 - 1556
Check for updates
Copyright
Copyright © Cambridge University Press 2016 

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

Adams, M., Li, Y., Khot, H., De Kock, C., Smith, P. J., Land, K., Chibale, K. and Smith, G. S. (2013). The synthesis and antiparasitic activity of aryl- and ferrocenyl-derived thiosemicarbazone ruthenium(II)-arene complexes. Dalton Transactions 42, 4677–4685.Google Scholar
Adams, M., de Kock, C., Smith, P. J., Land, K. M., Liu, N., Hopper, M., Hsiao, A., Burgoyne, A. R., Stringer, T., Meyer, M., Wiesner, L., Chibale, K. and Smith, G. S. (2015). Improved antiparasitic activity by incorporation of organosilane entities into half-sandwich ruthenium(II) and rhodium(III) thiosemicarbazone complexes. Dalton Transactions 44, 2456–2468.Google Scholar
Barbosa, M. I., Corrêa, R. S., de Oliveira, K. M., Rodrigues, C., Ellena, J., Nascimento, O. R., Rocha, V. P., Nonato, F. R., Macedo, T. S., Barbosa-Filho, J. M., Soares, M. B. and Batista, A. A. (2014). Antiparasitic activities of novel ruthenium/lapachol complexes. Journal of Inorganic Biochemistry 136, 33–39.Google Scholar
Cevenini, L., Camarda, G., Michelini, E., Siciliano, G., Calabretta, M. M., Bona, R., Kumar, T. R., Cara, A., Branchini, B. R., Fidock, D. A., Roda, A. and Alano, P. (2014). Multicolor bioluminescence boosts malaria research: quantitative dual-color assay and single-cell imaging in Plasmodium falciparum parasites. Analytical Chemistry 86, 8814–8821.Google Scholar
Chellan, P., Land, K. M., Shokar, A., Au, A., An, S. H., Taylor, D., Smith, P. J., Riedel, T., Dyson, P. J., Chibale, K. and Smith, G. S. (2014). Synthesis and evaluation of new polynuclear organometallic Ru(II), Rh(III) and Ir(III) pyridyl ester complexes as in vitro antiparasitic and antitumor agents. Dalton Transactions 43, 513–526.CrossRefGoogle ScholarPubMed
Clavel, C. M., Păunescu, E., Nowak-Sliwinska, P., Griffioen, A. W., Scopelliti, R. and Dyson, P. J. (2015). Modulating the anticancer activity of ruthenium(II)-arene complexes. Journal of Medicinal Chemistry 58, 3356–3365.Google Scholar
Colina-Vegas, L., Villarreal, W., Navarro, M., de Oliveira, C. R., Graminha, A. E., Maia, P. I., Deflon, V. M., Ferreira, A. G., Cominetti, M. R. and Batista, A. A. (2015). Cytotoxicity of Ru(II) piano-stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: interactions with DNA and BSA. Journal of Inorganic Biochemistry 153, 150–161.Google Scholar
D'Alessandro, S., Silvestrini, F., Dechering, K., Corbett, Y., Parapini, S., Timmerman, M., Galastri, L., Basilico, N., Sauerwein, R., Alano, P. and Taramelli, D. (2013). A Plasmodium falciparum screening assay for anti-gametocyte drugs based on parasite lactate dehydrogenase detection. Journal of Antimicrobial Chemotherapy 68, 2048–2058.Google Scholar
Dubar, F., Egan, T. J., Pradines, B., Kuter, D., Ncokazi, K. K., Forge, D., Paul, J. F., Pierrot, C., Kalamou, H., Khalife, J., Buisine, E., Rogier, C., Vezin, H., Forfar, I., Slomianny, C., Trivelli, X., Kapishnikov, S., Leiserowitz, L., Dive, D. and Biot, C. (2011). The antimalarial ferroquine: role of the metal and intramolecular hydrogen bond in activity and resistance. ACS Chemical Biology 6, 275–287.Google Scholar
Dubar, F., Slomianny, C., Khalife, J., Dive, D., Kalamou, H., Guérardel, Y., Grellier, P. and Biot, C. (2013). The ferroquine antimalarial conundrum: redox activation and reinvasion inhibition. Angewandte Chemie International Edition in English 52, 7690–7693.Google Scholar
Egan, T. J., Ross, D. C. and Adams, P. A. (1994). Quinoline anti-malarial drugs inhibit spontaneous formation of beta-haematin (malaria pigment). FEBS Letters 352, 54–57.Google Scholar
Egan, T. J., Mavuso, W. W., Ross, D. C. and Marques, H. M. (1997). Thermodynamic factors controlling the interaction of quinoline antimalarial drugs with ferriprotoporphyrin IX. Journal of Inorganic Biochemistry 68, 137–145.Google Scholar
Ekengard, E., Glans, L., Cassells, I., Fogeron, T., Govender, P., Stringer, T., Chellan, P., Lisensky, G. C., Hersh, W. H., Doverbratt, I., Lidin, S., de Kock, C., Smith, P. J., Smith, G. S. and Nordlander, E. (2015). Antimalarial activity of ruthenium(ii) and osmium(ii) arene complexes with mono- and bidentate chloroquine analogue ligands. Dalton Transactions 44, 19314–19329.Google Scholar
Fu, Y., Tilley, L., Kenny, S. and Klonis, N. (2010). Dual labeling with a far red probe permits analysis of growth and oxidative stress in P. falciparum-infected erythrocytes. Cytometry Part A. 77, 253–263.Google Scholar
Gabbiani, C., Messori, L., Cinellu, M. A., Casini, A., Mura, P., Sannella, A. R., Severini, C., Majori, G., Bilia, A. R. and Vincieri, F. F. (2009). Outstanding plasmodicidal properties within a small panel of metallic compounds: hints for the development of new metal-based antimalarials. Journal of Inorganic Biochemistry 103, 310–312.Google Scholar
Glans, L., Taylor, D., de Kock, C., Smith, P. J., Haukka, M., Moss, J. R. and Nordlander, E. (2011). Synthesis, characterization and antimalarial activity of new chromium arene-quinoline half sandwich complexes. Journal of Inorganic Biochemistry 105, 985–990.Google Scholar
Glans, L., Ehnbom, A., de Kock, C., Martínez, A., Estrada, J., Smith, P. J., Haukka, M., Sánchez-Delgado, R. A. and Nordlander, E. (2012 a). Ruthenium(II) arene complexes with chelating chloroquine analogue ligands: synthesis, characterization and in vitro antimalarial activity. Dalton Transactions 41, 2764–2773.Google Scholar
Glans, L., Hu, W., Jöst, C., de Kock, C., Smith, P. J., Haukka, M., Bruhn, H., Schatzschneider, U. and Nordlander, E. (2012 b ). Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis. Dalton Transactions 41, 6443–6450.Google Scholar
Goldberg, D. E., Sharma, V., Oksman, A., Gluzman, I. Y., Wellems, T. E. and Piwnica-Worms, D. (1997). Probing the chloroquine resistance locus of Plasmodium falciparum with a novel class of multidentate metal(III) coordination complexes. Journal of Biological Chemistry 272, 6567–6572.Google Scholar
Huta, B. P., Mehlenbacher, M. R., Nie, Y., Lai, X., Zubieta, C., Bou-Abdallah, F. and Doyle, R. P. (2016). The lysosomal protein saposin B binds chloroquine. ChemMedChem 11, 277–282.Google Scholar
Khanye, S. D., Smith, G. S., Lategan, C., Smith, P. J., Gut, J, Rosenthal, P. J. and Chibale, K. (2010). Synthesis and in vitro evaluation of gold(I) thiosemicarbazone complexes for antimalarial activity. Journal of Inorganic Biochemistry 104, 1079–1083.Google Scholar
Lewis, M. D., Behrends, J., Sá, E., Cunha, C., Mendes, A. M., Lasitschka, F., Sattler, J. M., Heiss, K., Kooij, T. W., Navarro, M., Pérez, H. and Sánchez-Delgado, R. A. (1997). Toward a novel metal-based chemotherapy against tropical diseases. 3. Synthesis and antimalarial activity in vitro and in vivo of the new gold-chloroquine complex [Au(PPh3)(CQ)]PF6. Journal of Medicinal Chemistry 40, 1937–1939.Google Scholar
Lin, J. W., Spaccapelo, R., Schwarzer, E., Sajid, M., Annoura, T., Deroost, K., Ravelli, R. B., Aime, E., Capuccini, B., Mommaas-Kienhuis, A. M., O'Toole, T., Prins, F., Franke-Fayard, B. M., Ramesar, J., Chevalley-Maurel, S., Kroeze, H., Koster, A. J., Tanke, H. J., Crisanti, A., Langhorne, J., Arese, P., Van den Steen, P. E., Janse, C. J. and Khan, S. M. (2015). Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance. Journal of Experimental Medicine 212, 893–903.Google Scholar
Martínez, A., Rajapakse, C. S., Jalloh, D., Dautriche, C. and Sánchez-Delgado, R. A. (2009). The antimalarial activity of Ru-chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces. Journal of Biological Inorganic Chemistry 14, 863–871.CrossRefGoogle ScholarPubMed
Martínez, A., Suárez, J., Shand, T., Magliozzo, R. S. and Sánchez-Delgado, R. A. (2011). Interactions of arene-Ru(II)-chloroquine complexes of known antimalarial and antitumor activity with human serum albumin (HSA) and transferrin. Journal of Inorganic Biochemistry 105, 39–45.Google Scholar
Maschke, M., Alborzinia, H., Lieb, M., Wölfl, S. and Metzler-Nolte, N. (2014). Structure-activity relationship of trifluoromethyl-containing metallocenes: electrochemistry, lipophilicity, cytotoxicity, and ROS production. ChemMedChem 9, 1188–1194.CrossRefGoogle ScholarPubMed
Meier, S. M., Novak, M., Kandioller, W., Jakupec, M. A., Arion, V. B., Metzler-Nolte, N., Keppler, B. K. and Hartinger, C. G. (2013). Identification of the structural determinants for anticancer activity of a ruthenium arene peptide conjugate. Chemistry 19, 9297–9307.CrossRefGoogle ScholarPubMed
Navarro, M., Vásquez, F., Sánchez-Delgado, R. A., Pérez, H., Sinou, V. and Schrével, J. (2004). Toward a novel metal-based chemotherapy against tropical diseases. 7. Synthesis and in vitro antimalarial activity of new gold-chloroquine complexes. Journal of Medicinal Chemistry 47, 5204–209.Google Scholar
Navarro, M., Castro, W., Higuera-Padilla, A. R., Sierraalta, A., Abad, M. J., Taylor, P. and Sánchez-Delgado, R. A. (2011 a). Synthesis, characterization and biological activity of trans-platinum(II) complexes with chloroquine. Journal of Inorganic Biochemistry 105, 1684–1691.Google Scholar
Navarro, M., Castro, W., Martínez, A. and Sánchez Delgado, R. A. (2011 b). The mechanism of antimalarial action of [Au(CQ)(PPh(3))]PF(6): structural effects and increased drug lipophilicity enhance heme aggregation inhibition at lipid/water interfaces. Journal of Inorganic Biochemistry 105, 276–282.Google Scholar
Navarro, M., Castro, W., Madamet, M., Amalvict, R., Benoit, N. and Pradines, B. (2014). Metal-chloroquine derivatives as possible anti-malarial drugs: evaluation of anti-malarial activity and mode of action. Malaria Journal 13, 471.Google Scholar
Nilsson, S. K., Childs, L. M., Buckee, C. and Marti, M. (2015). Targeting human transmission biology for malaria elimination. PLoS Pathogens 11, e1004871.CrossRefGoogle ScholarPubMed
Parapini, S., Basilico, N., Pasini, E., Egan, T. J., Olliaro, P., Taramelli, D. and Monti, D. (2000). Standardization of the physicochemical parameters to assess in vitro the beta-hematin inhibitory activity of antimalarial drugs. Experimental Parasitology 96, 249–256.Google Scholar
Peacock, A. F. and Sadler, P. J. (2008). Medicinal organometallic chemistry: designing metal arene complexes as anticancer agents. Chemistry Asian Journal 3, 1890–1189.Google Scholar
Pérez, B. C., Teixeira, C., Albuquerque, I. S., Gut, J., Rosenthal, P. J., Gomes, J. R., Prudêncio, M. and Gomes, P. (2013). N-cinnamoylated chloroquine analogues as dual-stage antimalarial leads. Journal of Medicinal Chemistry 56, 556–567.Google Scholar
Petersen, I., Eastman, R. and Lanzer, M. (2011). Drug-resistant malaria: molecular mechanisms and implications for public health. FEBS Letters 585, 1551–1562.Google Scholar
Ploemen, I. H., Prudêncio, M., Douradinha, B. G., Ramesar, J., Fonager, J., van Gemert, G. J., Luty, A. J., Hermsen, C. C., Sauerwein, R. W., Baptista, F. G., Mota, M. M., Waters, A. P., Que, I., Lowik, C. W., Khan, S. M., Janse, C. J. and Franke-Fayard, B. M. (2009). Visualisation and quantitative analysis of the rodent malaria liver stage by real time imaging. Plos ONE 4, e7881.Google Scholar
Price, R. N., von Seidlein, L., Valecha, N., Nosten, F., Baird, J. K. and White, N. J. (2014). Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infectious Diseases 14, 982–991.Google Scholar
Prudêncio, M., Rodriguez, A. and Mota, M. M. (2006). The silent path to thousands of merozoites: the Plasmodium liver stage. Nature Reviews Microbiology 4, 849–856.Google Scholar
Prudêncio, M., Mota, M. M. and Mendes, A. M. (2011). A toolbox to study liver stage malaria. Trends in Parasitology 27, 565–574.Google Scholar
Prudêncio, M., Bringmann, G., Frischknecht, F. and Mueller, A. K. (2015). Chemical attenuation of Plasmodium in the liver modulates severe malaria disease progression. Journal of Immunology. 194, 4860–4870.Google Scholar
Rajapakse, C. S., Martínez, A., Naoulou, B., Jarzecki, A. A., Suárez, L., Deregnaucourt, C., Sinou, V., Schrével, J., Musi, E., Ambrosini, G., Schwartz, G. K. and Sánchez-Delgado, R. A. (2009). Synthesis, characterization, and in vitro antimalarial and antitumor activity of new ruthenium(II) complexes of chloroquine. Inorganic Chemistry 48, 1122–1131.Google Scholar
Rodrigues, T., Prudêncio, M., Moreira, R., Mota, M. M. and Lopes, L. (2012). Targeting the liver stage of malaria parasites: a yet unmet goal. Journal of Medicinal Chemistry 55, 995–1012.Google Scholar
Salas, P. F., Herrmann, C., Cawthray, J. F., Nimphius, C., Kenkel, A., Chen, J., de Kock, C., Smith, P. J., Patrick, B. O., Adam, M. J. and Orvig, C. (2013). Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms. Journal of Medicinal Chemistry 56, 1596–1613.Google Scholar
Sánchez-Delgado, R. A., Navarro, M., Pérez, H. and Urbina, J. A. (1996). Toward a novel metal-based chemotherapy against tropical diseases. 2. Synthesis and antimalarial activity in vitro and in vivo of new ruthenium- and rhodium-chloroquine complexes. Journal of Medicinal Chemistry 39, 1095–1099.Google Scholar
Scovill, J. P., Klayman, D. L. and Franchino, C. F. (1982). 2-Acetylpyridine thiosemicarbazones. 4. Complexes with transition metals as antimalarial and antileukemic agents. Journal of Medicinal Chemistry 25, 1261–1264.Google Scholar
Stone, W., Gonçalves, B. P., Bousema, T. and Drakeley, C. (2015). Assessing the infectious reservoir of falciparum malaria: past and future. Trends in Parasitology 31, 287–296.Google Scholar
WHO Global Malaria Programme. World Malaria Report (2015), World Health Organization, Geneva, 2015. http://apps.who.int/iris/bitstream/10665/200018/1/9789241565158_eng.pdf?ua=1 Google Scholar
Supplementary material: File

Macedo supplementary material

Table S1 and Figures S1-S5

Download Macedo supplementary material(File)
File 2 MB