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In vitro anti-Trypanosoma cruzi activity enhancement of curcumin by its monoketone tetramethoxy analog diveratralacetone

Chagas disease is a tropical disease caused by the protozoan parasite Trypanosoma cruzi and currently affects millions of people worldwide. Curcumin (CUR), the major constituent of turmeric spice (dry powder of Curcuma longa L. plant rhizomes and roots), exhibits antiparasitic activity against proto...

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Autores principales: Souza, Julia M., Vieira, Tatiana M., Candido, Ana Carolina B.B., Tezuka, Daiane Y., Rao, G. Subba, de Albuquerque, Sérgio, Crotti, Antônio E.M., Siqueira-Neto, Jair L., Magalhães, Lizandra G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906099/
https://www.ncbi.nlm.nih.gov/pubmed/35284878
http://dx.doi.org/10.1016/j.crpvbd.2021.100031
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author Souza, Julia M.
Vieira, Tatiana M.
Candido, Ana Carolina B.B.
Tezuka, Daiane Y.
Rao, G. Subba
de Albuquerque, Sérgio
Crotti, Antônio E.M.
Siqueira-Neto, Jair L.
Magalhães, Lizandra G.
author_facet Souza, Julia M.
Vieira, Tatiana M.
Candido, Ana Carolina B.B.
Tezuka, Daiane Y.
Rao, G. Subba
de Albuquerque, Sérgio
Crotti, Antônio E.M.
Siqueira-Neto, Jair L.
Magalhães, Lizandra G.
author_sort Souza, Julia M.
collection PubMed
description Chagas disease is a tropical disease caused by the protozoan parasite Trypanosoma cruzi and currently affects millions of people worldwide. Curcumin (CUR), the major constituent of turmeric spice (dry powder of Curcuma longa L. plant rhizomes and roots), exhibits antiparasitic activity against protozoan parasites in vitro. However, because of its chemical instability, poor cellular uptake and limited bioavailability it is not suitable for clinical use. The objective of this study was to synthesize and evaluate in vitro CUR monoketone analog dibenzalacetone (DBA 1) and its non-phenolic, methoxy (2–4) and chloro (5) derivatives for better stability and bioavailability against T. cruzi. Diveratralacetone, the tetramethoxy DBA (DBA 3), was found to be the CUR analog with most enhanced activity against the amastigote forms of four strains of T. cruzi tested (Brazil, CA-I/72, Sylvio X10/4 and Sylvio X10/7) with 50% inhibitory concentration (IC(50)) < 10 μM (1.51–9.63 μM) and selectivity index (SI) > 10 (C2C12 non-infected mammalian cells). This was supplemented by time-course assessment of its anti-T. cruzi activity. DBA 1 and its dimethoxy (DBA 2) and hexamethoxy (DBA 4) derivatives were substantially less active. The inactivity of dichloro-DBA (DBA 5) was indicative of the important role played by oxygenated groups such as methoxy in the terminal aromatic rings in the DBA molecule, particularly at para position to form reactive oxygen species essential for anti-T. cruzi activity. Although the DBAs and CUR were toxic to infected mammalian cells in vitro, in a mouse model, both DBA 3 and CUR did not exhibit acute toxicity or mortality. These results justify further optimization and in vivo anti-T. cruzi activity evaluation of the inexpensive diveratralacetone for its potential use in treating Chagas disease, a neglected parasitic disease in economically challenged tropical countries.
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spelling pubmed-89060992022-03-10 In vitro anti-Trypanosoma cruzi activity enhancement of curcumin by its monoketone tetramethoxy analog diveratralacetone Souza, Julia M. Vieira, Tatiana M. Candido, Ana Carolina B.B. Tezuka, Daiane Y. Rao, G. Subba de Albuquerque, Sérgio Crotti, Antônio E.M. Siqueira-Neto, Jair L. Magalhães, Lizandra G. Curr Res Parasitol Vector Borne Dis Research Article Chagas disease is a tropical disease caused by the protozoan parasite Trypanosoma cruzi and currently affects millions of people worldwide. Curcumin (CUR), the major constituent of turmeric spice (dry powder of Curcuma longa L. plant rhizomes and roots), exhibits antiparasitic activity against protozoan parasites in vitro. However, because of its chemical instability, poor cellular uptake and limited bioavailability it is not suitable for clinical use. The objective of this study was to synthesize and evaluate in vitro CUR monoketone analog dibenzalacetone (DBA 1) and its non-phenolic, methoxy (2–4) and chloro (5) derivatives for better stability and bioavailability against T. cruzi. Diveratralacetone, the tetramethoxy DBA (DBA 3), was found to be the CUR analog with most enhanced activity against the amastigote forms of four strains of T. cruzi tested (Brazil, CA-I/72, Sylvio X10/4 and Sylvio X10/7) with 50% inhibitory concentration (IC(50)) < 10 μM (1.51–9.63 μM) and selectivity index (SI) > 10 (C2C12 non-infected mammalian cells). This was supplemented by time-course assessment of its anti-T. cruzi activity. DBA 1 and its dimethoxy (DBA 2) and hexamethoxy (DBA 4) derivatives were substantially less active. The inactivity of dichloro-DBA (DBA 5) was indicative of the important role played by oxygenated groups such as methoxy in the terminal aromatic rings in the DBA molecule, particularly at para position to form reactive oxygen species essential for anti-T. cruzi activity. Although the DBAs and CUR were toxic to infected mammalian cells in vitro, in a mouse model, both DBA 3 and CUR did not exhibit acute toxicity or mortality. These results justify further optimization and in vivo anti-T. cruzi activity evaluation of the inexpensive diveratralacetone for its potential use in treating Chagas disease, a neglected parasitic disease in economically challenged tropical countries. Elsevier 2021-05-31 /pmc/articles/PMC8906099/ /pubmed/35284878 http://dx.doi.org/10.1016/j.crpvbd.2021.100031 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Souza, Julia M.
Vieira, Tatiana M.
Candido, Ana Carolina B.B.
Tezuka, Daiane Y.
Rao, G. Subba
de Albuquerque, Sérgio
Crotti, Antônio E.M.
Siqueira-Neto, Jair L.
Magalhães, Lizandra G.
In vitro anti-Trypanosoma cruzi activity enhancement of curcumin by its monoketone tetramethoxy analog diveratralacetone
title In vitro anti-Trypanosoma cruzi activity enhancement of curcumin by its monoketone tetramethoxy analog diveratralacetone
title_full In vitro anti-Trypanosoma cruzi activity enhancement of curcumin by its monoketone tetramethoxy analog diveratralacetone
title_fullStr In vitro anti-Trypanosoma cruzi activity enhancement of curcumin by its monoketone tetramethoxy analog diveratralacetone
title_full_unstemmed In vitro anti-Trypanosoma cruzi activity enhancement of curcumin by its monoketone tetramethoxy analog diveratralacetone
title_short In vitro anti-Trypanosoma cruzi activity enhancement of curcumin by its monoketone tetramethoxy analog diveratralacetone
title_sort in vitro anti-trypanosoma cruzi activity enhancement of curcumin by its monoketone tetramethoxy analog diveratralacetone
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906099/
https://www.ncbi.nlm.nih.gov/pubmed/35284878
http://dx.doi.org/10.1016/j.crpvbd.2021.100031
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