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Development of a caffeic acid–phthalimide hybrid compound for NADPH oxidase inhibition

NADPH oxidases are pharmacological targets for the treatment of inflammation-based diseases. This work presents the synthesis and study of a caffeic acid/phthalimide hybrid compound (C2) as a potential inhibitor of NADPH oxidases. Throughout the study, we have compared compound C2 with its precursor...

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Autores principales: dos Santos, Willian Henrique, Yoguim, Maurício Ikeda, Daré, Regina Gomes, da Silva-Filho, Luiz Carlos, Lautenschlager, Sueli Oliveira Silva, Ximenes, Valdecir Farias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9033209/
https://www.ncbi.nlm.nih.gov/pubmed/35480205
http://dx.doi.org/10.1039/d1ra01066b
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author dos Santos, Willian Henrique
Yoguim, Maurício Ikeda
Daré, Regina Gomes
da Silva-Filho, Luiz Carlos
Lautenschlager, Sueli Oliveira Silva
Ximenes, Valdecir Farias
author_facet dos Santos, Willian Henrique
Yoguim, Maurício Ikeda
Daré, Regina Gomes
da Silva-Filho, Luiz Carlos
Lautenschlager, Sueli Oliveira Silva
Ximenes, Valdecir Farias
author_sort dos Santos, Willian Henrique
collection PubMed
description NADPH oxidases are pharmacological targets for the treatment of inflammation-based diseases. This work presents the synthesis and study of a caffeic acid/phthalimide hybrid compound (C2) as a potential inhibitor of NADPH oxidases. Throughout the study, we have compared compound C2 with its precursor caffeic acid (C1). The redox properties were compared using three different antioxidant methodologies and showed that C2 was slightly less effective than C1, a well-established and robust antioxidant. However, C2 was three-fold more effective than albumin (used as a model protein). This chemical feature was decisive for the higher efficiency of C2 as an inhibitor of the release of superoxide anions by stimulated neutrophils and enzymatic activity of cell-free NADPH oxidase. Docking simulation studies were performed using the crystal structure of the recombinant dehydrogenase domain of the isoform NOX5 of C. stagnale, which retains the FAD cofactor (PDB: 5O0X). Considering that C2 could bind at the FAD redox site of NOX5, studies were conducted by comparing the interactions and binding energies of C1 and C2. The binding energies were −50.30 (C1) and −74.88 (C2) (kJ mol(−1)), which is in agreement with the higher efficacy of the latter as an NADPH oxidase inhibitor. In conclusion, incorporating the phthalimide moiety into caffeic acid was decisive for its effectiveness as an NADPH oxidase inhibitor.
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spelling pubmed-90332092022-04-26 Development of a caffeic acid–phthalimide hybrid compound for NADPH oxidase inhibition dos Santos, Willian Henrique Yoguim, Maurício Ikeda Daré, Regina Gomes da Silva-Filho, Luiz Carlos Lautenschlager, Sueli Oliveira Silva Ximenes, Valdecir Farias RSC Adv Chemistry NADPH oxidases are pharmacological targets for the treatment of inflammation-based diseases. This work presents the synthesis and study of a caffeic acid/phthalimide hybrid compound (C2) as a potential inhibitor of NADPH oxidases. Throughout the study, we have compared compound C2 with its precursor caffeic acid (C1). The redox properties were compared using three different antioxidant methodologies and showed that C2 was slightly less effective than C1, a well-established and robust antioxidant. However, C2 was three-fold more effective than albumin (used as a model protein). This chemical feature was decisive for the higher efficiency of C2 as an inhibitor of the release of superoxide anions by stimulated neutrophils and enzymatic activity of cell-free NADPH oxidase. Docking simulation studies were performed using the crystal structure of the recombinant dehydrogenase domain of the isoform NOX5 of C. stagnale, which retains the FAD cofactor (PDB: 5O0X). Considering that C2 could bind at the FAD redox site of NOX5, studies were conducted by comparing the interactions and binding energies of C1 and C2. The binding energies were −50.30 (C1) and −74.88 (C2) (kJ mol(−1)), which is in agreement with the higher efficacy of the latter as an NADPH oxidase inhibitor. In conclusion, incorporating the phthalimide moiety into caffeic acid was decisive for its effectiveness as an NADPH oxidase inhibitor. The Royal Society of Chemistry 2021-05-18 /pmc/articles/PMC9033209/ /pubmed/35480205 http://dx.doi.org/10.1039/d1ra01066b Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
dos Santos, Willian Henrique
Yoguim, Maurício Ikeda
Daré, Regina Gomes
da Silva-Filho, Luiz Carlos
Lautenschlager, Sueli Oliveira Silva
Ximenes, Valdecir Farias
Development of a caffeic acid–phthalimide hybrid compound for NADPH oxidase inhibition
title Development of a caffeic acid–phthalimide hybrid compound for NADPH oxidase inhibition
title_full Development of a caffeic acid–phthalimide hybrid compound for NADPH oxidase inhibition
title_fullStr Development of a caffeic acid–phthalimide hybrid compound for NADPH oxidase inhibition
title_full_unstemmed Development of a caffeic acid–phthalimide hybrid compound for NADPH oxidase inhibition
title_short Development of a caffeic acid–phthalimide hybrid compound for NADPH oxidase inhibition
title_sort development of a caffeic acid–phthalimide hybrid compound for nadph oxidase inhibition
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9033209/
https://www.ncbi.nlm.nih.gov/pubmed/35480205
http://dx.doi.org/10.1039/d1ra01066b
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