Síntese e avaliação da atividade antileishmanial in vitro de bioisósteros do resveratrol
DOI:
https://doi.org/10.34019/2179-3700.2018.v18.29863Palavras-chave:
Leishmania sp., Bioisósteros, Resveratrol, TratamentoResumo
As leishmanioses são infecções causadas por protozoários do gênero Leishmania, responsáveis por altas taxas de morbidade e mortalidade em todo mundo. O tratamento está restrito a um número limitado de fármacos com alta toxicidade, variabilidade na eficácia e alto custo. Neste trabalho foram sintetizados quatro bioisósteros do resveratrol que foram avaliados em formas promastigotas de Leishmania amazonensis e L. braziliensis associadas à manifestação tegumentar da doença, além da citotoxicidade em macrófagos murinos. Dois dos compostos, 1a e 1b exibiram promissores resultados, com CI50 variando de 3,0 a 16,44 µM, e não apresentaram toxicidade em macrófagos peritoneais. O composto 1b exibiu o maior índice de seletividade (> 25) para ambas as espécies. Esses resultados indicam o potencial desta classe de compostos para o desenvolvimento de novos agentes antileishmaniais e estimulam a realização de estudos em amastigotas intracelulares e a avaliação do seu mecanismo de ação.
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Referências
AMEEN, M. Cutaneous leishmaniasis: advances in disease pathogenesis, diagnostics and
therapeutics. Clinical and Experimental Dermatology: Clinical Dermatology,
Portsmouth, v. 35, n. 7, p. 699-705, 2010.
BAE, S.J.H., et al.. Design, synthesis, and evaluation of (E)-N-substituted benzylideneaniline
derivatives as tyrosinase inhibitors. European Journal Medicinal Chemistry, v.
57, p. 383-390, 2012.
ULIANA, S. R. B. et al. Chemotherapy of leishmaniasis: present challenges. Parasitology,
Cambridge, v. 145, n. 5, p. 464-480, 2018.
WHO.Research priorities for Chagas disease, human African trypanosomiasis and
leishmaniasis. WHO, Geneva, Switzerland, 2012. Disponível em:
http://apps.who.int/iris/bitstream/handle/10665/77472/WHO_TRS_975_eng.pdf;jsessionid=
72CF7AFCE69E55FD52DE89DCCD1A5C11?sequence=1. Acessoem: 23 nov. 2018.
YARDLEY, V. et al. The sensitivity of clinical isolates of Leishmania from Peru and Nepal to
miltefosine. American Journal of Tropical Medicine and Hygiene, Cleveland, v. 73, n. 2,
p. 272-275, 2005.
XIA, N. et al. Antioxidant effects of resveratrol in the cardiovascular system. British
Journal of Pharmacology, Weinheim, v. 174, n. 12, p. 1633-1646, 2017.
COIMBRA, E. S. et al. Synthesis, antitubercular and leishmanicidal evaluation of
resveratrol analogues. Journal of the Brazilian Chemical Society, Campinas, v. 27, n.
12, p. 2161-2169, 2016.
DA SILVA, A. D. et al. Insights about resveratrol analogues against trypanothione
reductase of Leishmaniabraziliensis: molecular modeling, computational docking and in
vitro antileishmanial studies. Journal of Biomolecular Structure and Dynamics, p. 1-34,
2018.
DE MENEZES, J. P. B. et al. Advances in development of new treatment for
leishmaniasis. BioMed Research International, v. 2015, 2015.
DE PAULA, D. T. S et al. Synthesis, cytotoxicity and antileishmanial activity of aza-stilbene
derivatives. Mediterranean Journal of Chemistry, Kenitra, v. 2, n. 3, p. 493-502, 2013.
FAIRLAMB, A. H. et al. Trypanothione: a novel bis (glutathionyl) spermidine cofactor for
glutathione reductase in trypanosomatids. Science,Washington,v. 227, n. 4693, p. 1485-
1487, 1985.
FERREIRA, C. et al. Resveratrol is active against Leishmaniaamazonensis: in vitro effect
of its association with amphotericin B. Antimicrobial Agents and Chemotherapy,
Washington, v. 58, n.10, p. 6197-6298, 2014.
FRIEDMAN, H. L. Influence of Isosteric Replacements upon Biological Activity. National
Academy of Science, Washington, 1951, n. 206, p. 295.
KOUSHKI, M. et al. Resveratrol: A miraculous natural compound for diseases
treatment. Food Science & Nutrition, p. 1-18, 2018.
LAVORATO, S. N. et al. 1,3-Bis(aryloxy)propan-2-ols as potential antileishmanial
agents.Chemical Biology and Drug Design, Oxford, v. 90, n. 15, p. 981-986, 2017.
LIMA, L.M., BARREIRO, E.J. Bioisosterism: a useful strategy for molecular modification
and drug design. Current Medicinal Chemistry,Sharjah, v.12, p. 23-49, 2005.
MORAIS-TEIXEIRA, E.D. et al. The in vitro leishmanicidal activity of
hexadecylphosphocholine (miltefosine) against four medically relevant Leishmania species
of Brazil. Memórias do Instituto Oswaldo Cruz, Rio de Janeiro, v. 106, n. 4, p. 475-478,
2011.
MOSMANN, T. Rapid colorimetric assay for cellular growth and survival: application to
proliferation and cytotoxicity assays. Journal of Immunological Methods, v. 65, n. 1-2, p.
55-63, 1983.
PAREKH, P. et al. Downregulation of cyclin D1 is associated with decreased levels of p38
MAP kinases, Akt/PKB and Pak1 during chemopreventive effects of resveratrol in liver
cancer cells. Experimental and Toxicologic Pathology, v. 63, n. 1-2, p. 167-173, 2011.
PASSOS, C. L. A. et al. Leishmanicidal effect of synthetic trans-resveratrol analogs. PLoS
One,San Francisco, v. 10, n. 10, p. e0141778, 2015.
RUGANI, J.N. et al. Intraspecies susceptibility of Leishmania (Viannia) braziliensis to
antileishmanial drugs: Antimony resistance in human isolates from atypical lesions.
Biomedicine and Pharmacotherapy, v. 108, n. 2018, p. 1170-1180, 2018.
SILVEIRA, F.T. et al. Immunopathogenic competences of Leishmania (V.) braziliensis and
L. (L.) amazonensis in American cutaneous leishmaniasis.Parasite Immunology, v. 31, n.
8, p. 423-431, 2009.
SOLOMON, V. R. et al. Synthesis and antimalarial activity of side chain modified 4-
aminoquinoline derivatives. Journal of Medicinal Chemistry,Washington,v. 50, n. 2, p.
394-398, 2007.
TUNG, B. T. et al. Anti-inflammatory effect of resveratrol in old mice liver. Experimental Gerontology, v. 64, p. 1-7, 2015.
therapeutics. Clinical and Experimental Dermatology: Clinical Dermatology,
Portsmouth, v. 35, n. 7, p. 699-705, 2010.
BAE, S.J.H., et al.. Design, synthesis, and evaluation of (E)-N-substituted benzylideneaniline
derivatives as tyrosinase inhibitors. European Journal Medicinal Chemistry, v.
57, p. 383-390, 2012.
ULIANA, S. R. B. et al. Chemotherapy of leishmaniasis: present challenges. Parasitology,
Cambridge, v. 145, n. 5, p. 464-480, 2018.
WHO.Research priorities for Chagas disease, human African trypanosomiasis and
leishmaniasis. WHO, Geneva, Switzerland, 2012. Disponível em:
http://apps.who.int/iris/bitstream/handle/10665/77472/WHO_TRS_975_eng.pdf;jsessionid=
72CF7AFCE69E55FD52DE89DCCD1A5C11?sequence=1. Acessoem: 23 nov. 2018.
YARDLEY, V. et al. The sensitivity of clinical isolates of Leishmania from Peru and Nepal to
miltefosine. American Journal of Tropical Medicine and Hygiene, Cleveland, v. 73, n. 2,
p. 272-275, 2005.
XIA, N. et al. Antioxidant effects of resveratrol in the cardiovascular system. British
Journal of Pharmacology, Weinheim, v. 174, n. 12, p. 1633-1646, 2017.
COIMBRA, E. S. et al. Synthesis, antitubercular and leishmanicidal evaluation of
resveratrol analogues. Journal of the Brazilian Chemical Society, Campinas, v. 27, n.
12, p. 2161-2169, 2016.
DA SILVA, A. D. et al. Insights about resveratrol analogues against trypanothione
reductase of Leishmaniabraziliensis: molecular modeling, computational docking and in
vitro antileishmanial studies. Journal of Biomolecular Structure and Dynamics, p. 1-34,
2018.
DE MENEZES, J. P. B. et al. Advances in development of new treatment for
leishmaniasis. BioMed Research International, v. 2015, 2015.
DE PAULA, D. T. S et al. Synthesis, cytotoxicity and antileishmanial activity of aza-stilbene
derivatives. Mediterranean Journal of Chemistry, Kenitra, v. 2, n. 3, p. 493-502, 2013.
FAIRLAMB, A. H. et al. Trypanothione: a novel bis (glutathionyl) spermidine cofactor for
glutathione reductase in trypanosomatids. Science,Washington,v. 227, n. 4693, p. 1485-
1487, 1985.
FERREIRA, C. et al. Resveratrol is active against Leishmaniaamazonensis: in vitro effect
of its association with amphotericin B. Antimicrobial Agents and Chemotherapy,
Washington, v. 58, n.10, p. 6197-6298, 2014.
FRIEDMAN, H. L. Influence of Isosteric Replacements upon Biological Activity. National
Academy of Science, Washington, 1951, n. 206, p. 295.
KOUSHKI, M. et al. Resveratrol: A miraculous natural compound for diseases
treatment. Food Science & Nutrition, p. 1-18, 2018.
LAVORATO, S. N. et al. 1,3-Bis(aryloxy)propan-2-ols as potential antileishmanial
agents.Chemical Biology and Drug Design, Oxford, v. 90, n. 15, p. 981-986, 2017.
LIMA, L.M., BARREIRO, E.J. Bioisosterism: a useful strategy for molecular modification
and drug design. Current Medicinal Chemistry,Sharjah, v.12, p. 23-49, 2005.
MORAIS-TEIXEIRA, E.D. et al. The in vitro leishmanicidal activity of
hexadecylphosphocholine (miltefosine) against four medically relevant Leishmania species
of Brazil. Memórias do Instituto Oswaldo Cruz, Rio de Janeiro, v. 106, n. 4, p. 475-478,
2011.
MOSMANN, T. Rapid colorimetric assay for cellular growth and survival: application to
proliferation and cytotoxicity assays. Journal of Immunological Methods, v. 65, n. 1-2, p.
55-63, 1983.
PAREKH, P. et al. Downregulation of cyclin D1 is associated with decreased levels of p38
MAP kinases, Akt/PKB and Pak1 during chemopreventive effects of resveratrol in liver
cancer cells. Experimental and Toxicologic Pathology, v. 63, n. 1-2, p. 167-173, 2011.
PASSOS, C. L. A. et al. Leishmanicidal effect of synthetic trans-resveratrol analogs. PLoS
One,San Francisco, v. 10, n. 10, p. e0141778, 2015.
RUGANI, J.N. et al. Intraspecies susceptibility of Leishmania (Viannia) braziliensis to
antileishmanial drugs: Antimony resistance in human isolates from atypical lesions.
Biomedicine and Pharmacotherapy, v. 108, n. 2018, p. 1170-1180, 2018.
SILVEIRA, F.T. et al. Immunopathogenic competences of Leishmania (V.) braziliensis and
L. (L.) amazonensis in American cutaneous leishmaniasis.Parasite Immunology, v. 31, n.
8, p. 423-431, 2009.
SOLOMON, V. R. et al. Synthesis and antimalarial activity of side chain modified 4-
aminoquinoline derivatives. Journal of Medicinal Chemistry,Washington,v. 50, n. 2, p.
394-398, 2007.
TUNG, B. T. et al. Anti-inflammatory effect of resveratrol in old mice liver. Experimental Gerontology, v. 64, p. 1-7, 2015.
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Publicado
2020-03-05
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Silva, N. P. da, Antinarelli, L. M. R., Santos, J. A. dos, Silva, A. D. da, Meinel, R. S., Almeida, A. das C., Soares, R. P. P., & Coimbra, E. S. (2020). Síntese e avaliação da atividade antileishmanial in vitro de bioisósteros do resveratrol. Principia: Caminhos Da Iniciação Científica, 18(1), 10. https://doi.org/10.34019/2179-3700.2018.v18.29863
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