Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism
A drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level o...
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| Format: | Article |
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MDPI AG
2019-01-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/24/1/143 |
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| author | Rosivaldo S. Borges Ivanete C. Palheta Sirlene S. B. Ota Roberto B. Morais Valéria A. Barros Ryan S. Ramos Rai C. Silva Josivan da S. Costa Carlos H. T. P. Silva Joaquín M. Campos Cleydson B. R. Santos |
| author_facet | Rosivaldo S. Borges Ivanete C. Palheta Sirlene S. B. Ota Roberto B. Morais Valéria A. Barros Ryan S. Ramos Rai C. Silva Josivan da S. Costa Carlos H. T. P. Silva Joaquín M. Campos Cleydson B. R. Santos |
| author_sort | Rosivaldo S. Borges |
| collection | DOAJ |
| description | A drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level of theory, together with the 6-31+G(d,p) basis sets. Molecular orbital and ionization potential were associated to electron donation capacity. The spin densities contribution showed a preferential hydroxylation at the para-positions of phenyl ring when compared to other positions. In addition, on electron abstractions the aromatic hydroxylation has more impact than alkyl hydroxylation. Docking studies indicate that six structures 1, 7, 8 and 13–15 have potential for inhibiting human as well as murine COX-2, due to regions showing similar intermolecular interactions to the observed for the control compounds (indomethacin and refecoxib). Toxicity can be related to aromatic hydroxylation. In accordance to our calculations, the derivatives here proposed are potentially more active as well safer than phenylbutazone and only structures 8 and 13–15 were the most promising. Such results can explain the biological properties of phenylbutazone and support the design of potentially safer candidates. |
| first_indexed | 2024-12-12T22:57:14Z |
| format | Article |
| id | doaj.art-ba59a737c5154ceca4aa002f6e2ca0fe |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-12T22:57:14Z |
| publishDate | 2019-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-ba59a737c5154ceca4aa002f6e2ca0fe2022-12-22T00:08:55ZengMDPI AGMolecules1420-30492019-01-0124114310.3390/molecules24010143molecules24010143Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity MechanismRosivaldo S. Borges0Ivanete C. Palheta1Sirlene S. B. Ota2Roberto B. Morais3Valéria A. Barros4Ryan S. Ramos5Rai C. Silva6Josivan da S. Costa7Carlos H. T. P. Silva8Joaquín M. Campos9Cleydson B. R. Santos10Núcleo de Estudos e Seleção de Moléculas Bioativas—NESBio, College of Pharmacy, Health Sciences Institute, Federal University of Pará, Belém 66075-110, PA, BrazilNúcleo de Estudos e Seleção de Moléculas Bioativas—NESBio, College of Pharmacy, Health Sciences Institute, Federal University of Pará, Belém 66075-110, PA, BrazilNúcleo de Estudos e Seleção de Moléculas Bioativas—NESBio, College of Pharmacy, Health Sciences Institute, Federal University of Pará, Belém 66075-110, PA, BrazilNúcleo de Estudos e Seleção de Moléculas Bioativas—NESBio, College of Pharmacy, Health Sciences Institute, Federal University of Pará, Belém 66075-110, PA, BrazilNúcleo de Estudos e Seleção de Moléculas Bioativas—NESBio, College of Pharmacy, Health Sciences Institute, Federal University of Pará, Belém 66075-110, PA, BrazilPrograma de Pós-Graduação em Biodiversidade e Biotecnologia—Rede BIONORTE, Federal University of Amapá, Macapá 68902-280, AP, BrazilPrograma de Pós-Graduação em Química Medicinal e Modelagem Molecular, Health Science Institute, Federal University of Pará, Belém 66075-110, PA, BrazilLaboratorio de Modelagem e Química Computacional—LMQC, Federal University of Amapá, Department of Biological Sciences. Rod. Juscelino Kubitschek, Km 02, Macapá 68902-280, AP, BrazilLaboratório Computacional de Química Farmacêutica, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, University of Sao Paulo, São Paulo 14040-903, SP, BrazilDepartment of Pharmaceutical Organic Chemistry, University of Granada, 18071 Granada, SpainPrograma de Pós-Graduação em Química Medicinal e Modelagem Molecular, Health Science Institute, Federal University of Pará, Belém 66075-110, PA, BrazilA drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level of theory, together with the 6-31+G(d,p) basis sets. Molecular orbital and ionization potential were associated to electron donation capacity. The spin densities contribution showed a preferential hydroxylation at the para-positions of phenyl ring when compared to other positions. In addition, on electron abstractions the aromatic hydroxylation has more impact than alkyl hydroxylation. Docking studies indicate that six structures 1, 7, 8 and 13–15 have potential for inhibiting human as well as murine COX-2, due to regions showing similar intermolecular interactions to the observed for the control compounds (indomethacin and refecoxib). Toxicity can be related to aromatic hydroxylation. In accordance to our calculations, the derivatives here proposed are potentially more active as well safer than phenylbutazone and only structures 8 and 13–15 were the most promising. Such results can explain the biological properties of phenylbutazone and support the design of potentially safer candidates.http://www.mdpi.com/1420-3049/24/1/143phenylbutazoneDFTelectron transfermetabolismtoxicity |
| spellingShingle | Rosivaldo S. Borges Ivanete C. Palheta Sirlene S. B. Ota Roberto B. Morais Valéria A. Barros Ryan S. Ramos Rai C. Silva Josivan da S. Costa Carlos H. T. P. Silva Joaquín M. Campos Cleydson B. R. Santos Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism Molecules phenylbutazone DFT electron transfer metabolism toxicity |
| title | Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism |
| title_full | Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism |
| title_fullStr | Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism |
| title_full_unstemmed | Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism |
| title_short | Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism |
| title_sort | toward of safer phenylbutazone derivatives by exploration of toxicity mechanism |
| topic | phenylbutazone DFT electron transfer metabolism toxicity |
| url | http://www.mdpi.com/1420-3049/24/1/143 |
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