Avaliação in vitro da atividade antileishmania de complexos de cobre (I)
DOI:
https://doi.org/10.22571/2526-4338474Palavras-chave:
Bioensaios, Leishmania, leishmanioses, complexos metálicosResumo
Na busca do desenvolvimento de novos fármacos para a terapia da leishmaniose tegumentar americana, o cobre tem sido estudado quanto a sua atividade antileishmania. Esse estudo tem como objetivo relatar a atividade de três complexos de cobre (I) sobre parasitas das espécies L. amazonensis e L. guyanensis. Os complexos metálicos foram testados por meio de ensaios antileishmania in vitro contra as formas promastigota e amastigota das espécies mais prevalentes no estado do Amazonas, Brasil. A citotoxicidade dos complexos foi avaliada em linhagem de células semelhantes a macrófagos murinos (MJ774). Os resultados dos ensaios in vitro indicaram que, entre os complexos de cobre testados, o complexo homoléptico de fosfina [Cu(thp)4][PF6](thp=tris-hidroximetilfosfina) apresentou atividade promissora contra as formas evolutivas de L. amazonensis, e obtiveram IC50 de 26,45 e 24,61 µM em um período de 48 e 72 h, respectivamente. Os resultados para o complexo de cobre na concentração de 160 µM nas formas amastigotas reportaram diminuição no índice de infecção (32% das células infectadas) e, no ensaio de citotoxicidade com MJ774, observou-se 52,43% de viabilidade celular. Os resultados evidenciaram que o complexo [Cu(thp)4][PF6] apresentou atividade biológica significativa, indicando a necessidade de futuros estudos in vivo.
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Referências
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Blanco, V.R. and Nascimento-Júnior N.M. (2017). Leishmaniose: Aspectos gerais relacionados com a doença, o ciclo do parasita, fármacos disponíveis, novos protótipos e vacinas. Revista Virtual de Química, 9(3), 861-876. doi: 10.21577/1984-6835.20170055.
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Comandolli-Wyrepkowski, C. D., Jensen, B. B., Grafova, I., Santos, P. A., Barros, A. M. C., Soares, F. V., Barcellos, J. F. M., Silva, A. F., Grafov, A. and Franco, A. M. R. (2017). Antileishmanial activity of extracts from Libidibia ferrea: development of in vitro and in vivo tests. Acta Amazonica, 47(4), 331-340. doi: 10.1590/1809-4392201700871.
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Porchia, M., Benetollo, F., Refosco, F., Tisato, F., Marzano, C. and Gandin, V. (2009). Synthesis and structural characterization of copper(I) complexes bearing N-methyl-1,3,5-triaza-7-phosphaadamantane (mPTA): Cytotoxic activity evaluation of a series of water soluble Cu(I) derivatives containing PTA, PTAH and mPTA ligands. Journal of Inorganic Biochemistry, 103(12), 1644-1651. doi: 10.1016/j.jinorgbio.2009.09.005.
Portas, A. S., Miguel, D. C., Yokoyama-Yasunaka, J. K. U., Uliana, S. R B. and Espósito, B. P. (2012). Increasing the activity of copper(II) complexes against Leishmania through lipophilicity and pro-oxidant ability. Journal of Biological Inorganic Chemistry, 17, 107-112. doi: 10.1007/s00775-011-0834-3.
Puig, S. and Thiele, D. J. (2020). Molecular mechanisms of copper uptake and distribution. Current Opinion in Chemical Biology, 6(2), 171-180. doi: 10.1016/s1367-5931(02)00298-3.
Quaretti, M., Porchia, M., Tisato, F., Trapananti, A., Aquilanti, G., Damjanović, M., Marchiò, L., Giogertti, M. and Tegoni, M. (2018). Thermodynamic stability and structure in aqueous solution of the [Cu(PTA)4]+ complex (PTA = aminophosphine 1,3,5-triaza-7-phosphaadamantane). Journal of Inorganic Biochemistry, 188, 50-61. doi: 10.1016/j.jinorgbio.2018.08.008.
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Saeed, A., Larik, F. A., Jabeen, F., Mehfooz, H., Ghumro, S. A., El-Seedi, H.R., Ali., M., Channar, P. A. and Ashraf. H. (2018). Synthesis, antibacterial and antileishmanial activity, cytotoxicity, and molecular docking of new heteroleptic copper(I) complexes with thiourea ligands and triphenylphosphine. Russian Journal of General Chemistry, 88(3), 541–550. doi: 10.1134/S1070363218030246.
Selvaganapathy, M. and Raman, N., (2016). Pharmacological activity of a few transition metal complexes: a short review. Journal of Chemical Biology & Therapeutics, 1(2), 108. doi: 10.4172/2572-0406.1000108.
Sinan/SVS/MS [database on the Internet] Casos de Leishmaniose Tegumentar. Brasil, Grandes Regiões e Unidades Federadas. 1990 a 2018. Available in: https://portalarquivos2.saude.gov.br/images/pdf/2019/outubro/14/LT-Casos.pdf.
Singh, M. K, Bhaumik, S. K., Karmakar, S., Paul, J., Sawoo, S., Majumder, H.K. and Roy, A. (2017). Copper salisylaldoxime (CuSAL) imparts protective efficacy against visceral leishmaniasis by targeting Leishmania donovani topoisomerase IB. Experimental Parasitology, 175, 8-20. doi: 10.1016/j.exppara.2017.02.010.
Tahghighi, A. (2014). Importance of metal complexes for development of potential leishmanicidal agents. Journal of Organometallic Chemistry, 770, 51-60. doi: 10.1016/j.jorganchem.2014.08.007.
Tisato, F., Marzano, C., Peruzzo, V., Tegoni, M., Giorgetti, M., Damjanovic, M., Trapananti, A., Bagno, A., Santini, C., Pellei, M., Porchia, M. and Gandin, V. (2016). Insights into the cytotoxic activity of the phosphane copper(I) complex [Cu(thp)4][PF6]. Journal of Inorganic Biochemistry, 165, 80-91. doi: 10.1016/j.jinorgbio.2016.07.007.
Tunes, L. G., Morato, R. E., Garcia, A., Schmitz, V., Steindel, M., Côrrea-Junior, J. D., Santos, H. F. D., Frézard, F., Almeida, M. V., Silva, H., Moretti, N. S., Barros, A. L. B. and Monte-Neto, R. L. (2020). Preclinical gold complexes as oral drug candidates to treat leishmaniasis are potent trypanothione reductase inhibitors. ACS Infectious Disease, 6(5), 1121-1139. doi: 10.1021/acsinfecdis.9b00505.
WHO. World Health Organization [homepage on the Internet]. Leishmaniasis. Available in: https://www.who.int/health-topics/leishmaniasis#tab=tab_1.
Young, J. and Kima, P.E. (2019). The Leishmania parasitophorous vacuole membrane at the parasite-host interface. Yale Journal of Biology and Medicine, 92(3): 511-521. Recovered from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747952/
Bastos, M. M., Boechat, N., Hoelz, L. V. B. & de Oliveira, A. P. (2016). Quimioterapia antileishmania: Uma revisão bibliográfica. Revista Virtual de Química, 8(6), 2072-2104. doi: 10.21577/1984-6835.20160139.
Blanco, V.R. and Nascimento-Júnior N.M. (2017). Leishmaniose: Aspectos gerais relacionados com a doença, o ciclo do parasita, fármacos disponíveis, novos protótipos e vacinas. Revista Virtual de Química, 9(3), 861-876. doi: 10.21577/1984-6835.20170055.
Britta, E. A., Silva, A. P. B., Ueda-Nakamura, T., Dias-Filho, B. P., Silva, C. C., Sernaglia, R. L and Nakamura, C. V. (2012). Benzaldehyde thiosemicarbazone derived from limonene complexed with copper induced mitochondrial dysfunction in Leishmania amazonensis. PLoS ONE, 7(8), e41440. doi: 10.1371/journal.pone.0041440.
Comandolli-Wyrepkowski, C. D., Jensen, B. B., Grafova, I., Santos, P. A., Barros, A. M. C., Soares, F. V., Barcellos, J. F. M., Silva, A. F., Grafov, A. and Franco, A. M. R. (2017). Antileishmanial activity of extracts from Libidibia ferrea: development of in vitro and in vivo tests. Acta Amazonica, 47(4), 331-340. doi: 10.1590/1809-4392201700871.
Gandin, V., Tisato, F., Dolmella, A., Pellei, M., Santini, C., Giorgetti, M., Marzano, C. and Porchia, M. (2014). In vitro and in vivo anticancer activity of copper(I) complexes with homoscorpionate tridentate tris(pyrazolyl)borate and auxiliary monodentate phosphine ligands. Journal of Medicinal Chemistry, 57(11). doi:10.1021/jm500279x.
Jhingran, A., Chawla, B., Saxena, S., Barrett, M. P. and Madhubala, R. (2009). Paromomycin: uptake and resistance in Leishmania Donovani. Molecular and Biochemical Parasitology, 164(2), 111−117. doi: 10.1016/j.molbiopara.2008.12.007.
Marzano, C., Gandin, V. Pellei, M., Colavito, D., Papini, G., Lobbia, G.G., Giudice, E.D., Porchia, M. Tisato, F. and Santini, C. (2008). In vitro antitumor activity of the water soluble copper(I) complexes bearing the tris(hydroxymethyl)phosphine ligand. Journal of Medicinal Chemistry, 51(4), 798-808. doi: 10.1021/jm701146c.
Navarro, M., Cisneros-Fajardo, E. J., Fernandez-Mestre, M., Arrieche, D. and Marchan, E. (2003a). Synthesis, characterization, DNA binding study and biological activity against Leishmania mexicana of [Cu(dppz)2]BF4. Journal of Inorganic Biochemistry, 97(4), 364-369. doi: 10.1016/s0162-0134(03)00290-3.
Navarro, M., Cisneros-Fajardo, E. J., Sierralta, A., Fernández-Mestre, M., Silva, P., Arrieche, D. and Marchán, E. (2003b). Design of copper DNA intercalators with leishmanicidal activity. Journal of Biological Inorganic Chemistry, 8, 401-408. doi: 10.1007/s00775-002-0427-2.
Ong, Y. C., Roy, S., Andrews, P. C. and Gasser, G. (2019). Metal compounds against neglected tropical diseases. Chemical Reviews, 119(2), 730-796. doi: 10.1021/acs.chemrev.8b00338.
Porchia, M., Benetollo, F., Refosco, F., Tisato, F., Marzano, C. and Gandin, V. (2009). Synthesis and structural characterization of copper(I) complexes bearing N-methyl-1,3,5-triaza-7-phosphaadamantane (mPTA): Cytotoxic activity evaluation of a series of water soluble Cu(I) derivatives containing PTA, PTAH and mPTA ligands. Journal of Inorganic Biochemistry, 103(12), 1644-1651. doi: 10.1016/j.jinorgbio.2009.09.005.
Portas, A. S., Miguel, D. C., Yokoyama-Yasunaka, J. K. U., Uliana, S. R B. and Espósito, B. P. (2012). Increasing the activity of copper(II) complexes against Leishmania through lipophilicity and pro-oxidant ability. Journal of Biological Inorganic Chemistry, 17, 107-112. doi: 10.1007/s00775-011-0834-3.
Puig, S. and Thiele, D. J. (2020). Molecular mechanisms of copper uptake and distribution. Current Opinion in Chemical Biology, 6(2), 171-180. doi: 10.1016/s1367-5931(02)00298-3.
Quaretti, M., Porchia, M., Tisato, F., Trapananti, A., Aquilanti, G., Damjanović, M., Marchiò, L., Giogertti, M. and Tegoni, M. (2018). Thermodynamic stability and structure in aqueous solution of the [Cu(PTA)4]+ complex (PTA = aminophosphine 1,3,5-triaza-7-phosphaadamantane). Journal of Inorganic Biochemistry, 188, 50-61. doi: 10.1016/j.jinorgbio.2018.08.008.
Ren, F., Logeman, B.L., Zhang, X., Liu, Y., Thiele, D.J. and Yuan, P. (2019). X-ray structures of the high-affinity copper transporter Ctr1. Nature Communication, 10(1386). doi: 10.1038/s41467-019-09376-7.
Saeed, A., Larik, F. A., Jabeen, F., Mehfooz, H., Ghumro, S. A., El-Seedi, H.R., Ali., M., Channar, P. A. and Ashraf. H. (2018). Synthesis, antibacterial and antileishmanial activity, cytotoxicity, and molecular docking of new heteroleptic copper(I) complexes with thiourea ligands and triphenylphosphine. Russian Journal of General Chemistry, 88(3), 541–550. doi: 10.1134/S1070363218030246.
Selvaganapathy, M. and Raman, N., (2016). Pharmacological activity of a few transition metal complexes: a short review. Journal of Chemical Biology & Therapeutics, 1(2), 108. doi: 10.4172/2572-0406.1000108.
Sinan/SVS/MS [database on the Internet] Casos de Leishmaniose Tegumentar. Brasil, Grandes Regiões e Unidades Federadas. 1990 a 2018. Available in: https://portalarquivos2.saude.gov.br/images/pdf/2019/outubro/14/LT-Casos.pdf.
Singh, M. K, Bhaumik, S. K., Karmakar, S., Paul, J., Sawoo, S., Majumder, H.K. and Roy, A. (2017). Copper salisylaldoxime (CuSAL) imparts protective efficacy against visceral leishmaniasis by targeting Leishmania donovani topoisomerase IB. Experimental Parasitology, 175, 8-20. doi: 10.1016/j.exppara.2017.02.010.
Tahghighi, A. (2014). Importance of metal complexes for development of potential leishmanicidal agents. Journal of Organometallic Chemistry, 770, 51-60. doi: 10.1016/j.jorganchem.2014.08.007.
Tisato, F., Marzano, C., Peruzzo, V., Tegoni, M., Giorgetti, M., Damjanovic, M., Trapananti, A., Bagno, A., Santini, C., Pellei, M., Porchia, M. and Gandin, V. (2016). Insights into the cytotoxic activity of the phosphane copper(I) complex [Cu(thp)4][PF6]. Journal of Inorganic Biochemistry, 165, 80-91. doi: 10.1016/j.jinorgbio.2016.07.007.
Tunes, L. G., Morato, R. E., Garcia, A., Schmitz, V., Steindel, M., Côrrea-Junior, J. D., Santos, H. F. D., Frézard, F., Almeida, M. V., Silva, H., Moretti, N. S., Barros, A. L. B. and Monte-Neto, R. L. (2020). Preclinical gold complexes as oral drug candidates to treat leishmaniasis are potent trypanothione reductase inhibitors. ACS Infectious Disease, 6(5), 1121-1139. doi: 10.1021/acsinfecdis.9b00505.
WHO. World Health Organization [homepage on the Internet]. Leishmaniasis. Available in: https://www.who.int/health-topics/leishmaniasis#tab=tab_1.
Young, J. and Kima, P.E. (2019). The Leishmania parasitophorous vacuole membrane at the parasite-host interface. Yale Journal of Biology and Medicine, 92(3): 511-521. Recovered from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747952/
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2021-01-27
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Parasitologia
