Cargando…
Analgesic Activity of 5-Acetamido-2-Hydroxy Benzoic Acid Derivatives and an In-Vivo and In-Silico Analysis of Their Target Interactions
The design, synthesis, and evaluation of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are big challenges today. In this work, two 5-acetamido-2-hydroxy benzoic acid derivatives were proposed, increasing the alkyl position (methyl) in an acetamide m...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10674373/ https://www.ncbi.nlm.nih.gov/pubmed/38004449 http://dx.doi.org/10.3390/ph16111584 |
_version_ | 1785140812646973440 |
---|---|
author | Santos, Cleydson B. R. Lobato, Cleison C. Ota, Sirlene S. B. Silva, Rai C. Bittencourt, Renata C. V. S. Freitas, Jofre J. S. Ferreira, Elenilze F. B. Ferreira, Marília B. Silva, Renata C. De Lima, Anderson B. Campos, Joaquín M. Borges, Rosivaldo S. Bittencourt, José A. H. M. |
author_facet | Santos, Cleydson B. R. Lobato, Cleison C. Ota, Sirlene S. B. Silva, Rai C. Bittencourt, Renata C. V. S. Freitas, Jofre J. S. Ferreira, Elenilze F. B. Ferreira, Marília B. Silva, Renata C. De Lima, Anderson B. Campos, Joaquín M. Borges, Rosivaldo S. Bittencourt, José A. H. M. |
author_sort | Santos, Cleydson B. R. |
collection | PubMed |
description | The design, synthesis, and evaluation of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are big challenges today. In this work, two 5-acetamido-2-hydroxy benzoic acid derivatives were proposed, increasing the alkyl position (methyl) in an acetamide moiety, and synthesized, and their structural elucidation was performed using (1)H NMR and (13)C NMR. The changes in methyl in larger groups such as phenyl and benzyl aim to increase their selectivity over cyclooxygenase 2 (COX-2). These 5-acetamido-2-hydroxy benzoic acid derivatives were prepared using classic methods of acylation reactions with anhydride or acyl chloride. Pharmacokinetics and toxicological properties were predicted using computational tools, and their binding affinity (kcal/mol) with COX-2 receptors (Mus musculus and Homo sapiens) was analyzed using docking studies (PDB ID 4PH9, 5KIR, 1PXX and 5F1A). An in-silico study showed that 5-acetamido-2-hydroxy benzoic acid derivates have a better bioavailability and binding affinity with the COX-2 receptor, and in-vivo anti-nociceptive activity was investigated by means of a writhing test induced by acetic acid and a hot plate. PS3, at doses of 20 and 50 mg/kg, reduced painful activity by 74% and 75%, respectively, when compared to the control group (20 mg/kg). Regarding the anti-nociceptive activity, the benzyl showed reductions in painful activity when compared to acetaminophen and 5-acetamido-2-hydroxy benzoic acid. However, the proposed derivatives are potentially more active than 5-acetamido-2-hydroxy benzoic acid and they support the design of novel and safer derivative candidates. Consequently, more studies need to be conducted to evaluate the different pharmacological actions, the toxicity of possible metabolites that can be generated, and their potential use in inflammation and pain therapy. |
format | Online Article Text |
id | pubmed-10674373 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-106743732023-11-09 Analgesic Activity of 5-Acetamido-2-Hydroxy Benzoic Acid Derivatives and an In-Vivo and In-Silico Analysis of Their Target Interactions Santos, Cleydson B. R. Lobato, Cleison C. Ota, Sirlene S. B. Silva, Rai C. Bittencourt, Renata C. V. S. Freitas, Jofre J. S. Ferreira, Elenilze F. B. Ferreira, Marília B. Silva, Renata C. De Lima, Anderson B. Campos, Joaquín M. Borges, Rosivaldo S. Bittencourt, José A. H. M. Pharmaceuticals (Basel) Article The design, synthesis, and evaluation of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are big challenges today. In this work, two 5-acetamido-2-hydroxy benzoic acid derivatives were proposed, increasing the alkyl position (methyl) in an acetamide moiety, and synthesized, and their structural elucidation was performed using (1)H NMR and (13)C NMR. The changes in methyl in larger groups such as phenyl and benzyl aim to increase their selectivity over cyclooxygenase 2 (COX-2). These 5-acetamido-2-hydroxy benzoic acid derivatives were prepared using classic methods of acylation reactions with anhydride or acyl chloride. Pharmacokinetics and toxicological properties were predicted using computational tools, and their binding affinity (kcal/mol) with COX-2 receptors (Mus musculus and Homo sapiens) was analyzed using docking studies (PDB ID 4PH9, 5KIR, 1PXX and 5F1A). An in-silico study showed that 5-acetamido-2-hydroxy benzoic acid derivates have a better bioavailability and binding affinity with the COX-2 receptor, and in-vivo anti-nociceptive activity was investigated by means of a writhing test induced by acetic acid and a hot plate. PS3, at doses of 20 and 50 mg/kg, reduced painful activity by 74% and 75%, respectively, when compared to the control group (20 mg/kg). Regarding the anti-nociceptive activity, the benzyl showed reductions in painful activity when compared to acetaminophen and 5-acetamido-2-hydroxy benzoic acid. However, the proposed derivatives are potentially more active than 5-acetamido-2-hydroxy benzoic acid and they support the design of novel and safer derivative candidates. Consequently, more studies need to be conducted to evaluate the different pharmacological actions, the toxicity of possible metabolites that can be generated, and their potential use in inflammation and pain therapy. MDPI 2023-11-09 /pmc/articles/PMC10674373/ /pubmed/38004449 http://dx.doi.org/10.3390/ph16111584 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Santos, Cleydson B. R. Lobato, Cleison C. Ota, Sirlene S. B. Silva, Rai C. Bittencourt, Renata C. V. S. Freitas, Jofre J. S. Ferreira, Elenilze F. B. Ferreira, Marília B. Silva, Renata C. De Lima, Anderson B. Campos, Joaquín M. Borges, Rosivaldo S. Bittencourt, José A. H. M. Analgesic Activity of 5-Acetamido-2-Hydroxy Benzoic Acid Derivatives and an In-Vivo and In-Silico Analysis of Their Target Interactions |
title | Analgesic Activity of 5-Acetamido-2-Hydroxy Benzoic Acid Derivatives and an In-Vivo and In-Silico Analysis of Their Target Interactions |
title_full | Analgesic Activity of 5-Acetamido-2-Hydroxy Benzoic Acid Derivatives and an In-Vivo and In-Silico Analysis of Their Target Interactions |
title_fullStr | Analgesic Activity of 5-Acetamido-2-Hydroxy Benzoic Acid Derivatives and an In-Vivo and In-Silico Analysis of Their Target Interactions |
title_full_unstemmed | Analgesic Activity of 5-Acetamido-2-Hydroxy Benzoic Acid Derivatives and an In-Vivo and In-Silico Analysis of Their Target Interactions |
title_short | Analgesic Activity of 5-Acetamido-2-Hydroxy Benzoic Acid Derivatives and an In-Vivo and In-Silico Analysis of Their Target Interactions |
title_sort | analgesic activity of 5-acetamido-2-hydroxy benzoic acid derivatives and an in-vivo and in-silico analysis of their target interactions |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10674373/ https://www.ncbi.nlm.nih.gov/pubmed/38004449 http://dx.doi.org/10.3390/ph16111584 |
work_keys_str_mv | AT santoscleydsonbr analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT lobatocleisonc analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT otasirlenesb analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT silvaraic analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT bittencourtrenatacvs analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT freitasjofrejs analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT ferreiraelenilzefb analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT ferreiramariliab analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT silvarenatac analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT delimaandersonb analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT camposjoaquinm analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT borgesrosivaldos analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions AT bittencourtjoseahm analgesicactivityof5acetamido2hydroxybenzoicacidderivativesandaninvivoandinsilicoanalysisoftheirtargetinteractions |