Biopharmaceutical Profiling of New Antitumor Pyrazole Derivatives
Several new pyrazole derivatives have demonstrated promising antiproliferative and cytotoxic effects, but their poor solubility raised concerns over possible biopharmaceutical limitations. In order to improve their pharmaceutical potential we performed the biopharmaceutical profiling for nine pyrazo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2014-10-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/19/10/16381 |
| _version_ | 1818980653823164416 |
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| author | Valentina Anuta George Mihai Nitulescu Cristina Elena Dinu-Pîrvu Octavian Tudorel Olaru |
| author_facet | Valentina Anuta George Mihai Nitulescu Cristina Elena Dinu-Pîrvu Octavian Tudorel Olaru |
| author_sort | Valentina Anuta |
| collection | DOAJ |
| description | Several new pyrazole derivatives have demonstrated promising antiproliferative and cytotoxic effects, but their poor solubility raised concerns over possible biopharmaceutical limitations. In order to improve their pharmaceutical potential we performed the biopharmaceutical profiling for nine pyrazole compounds using in vitro and computational methods. The experimental solubility was determined in five different media using a validated HPLC method. Although the experimental solubility was lower than the predicted one, a good linear relationship was observed. The results also indicated a minimal impact of endogenous tensioactives on solubility, suggesting dissolution rate limited absorption. The in silico experiments were focused on identification of molecular determinants of solubility, evaluation of drug-likeness, prediction of in vivo absorption based on mechanistic models, as well as identification of the main factors that could impact on the oral bioavailability. The results suggested that dose, solubility and particle size are the main determinants of absorption, whereas permeability has little effect, confirming the BCS Class II behavior of the compounds. The present investigation was able to rank the tested compounds in terms of biopharmaceutical behavior, and indicated the B3 series compounds as having a more favorable absorption profile making them the main candidates for advance to the pre-clinical in vivo studies. |
| first_indexed | 2024-12-20T17:18:51Z |
| format | Article |
| id | doaj.art-caca0682ca97436890d2e0b3aa1f76ef |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-20T17:18:51Z |
| publishDate | 2014-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-caca0682ca97436890d2e0b3aa1f76ef2022-12-21T19:31:55ZengMDPI AGMolecules1420-30492014-10-011910163811640110.3390/molecules191016381molecules191016381Biopharmaceutical Profiling of New Antitumor Pyrazole DerivativesValentina Anuta0George Mihai Nitulescu1Cristina Elena Dinu-Pîrvu2Octavian Tudorel Olaru3Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, Bucharest 020956, RomaniaFaculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, Bucharest 020956, RomaniaFaculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, Bucharest 020956, RomaniaFaculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, Bucharest 020956, RomaniaSeveral new pyrazole derivatives have demonstrated promising antiproliferative and cytotoxic effects, but their poor solubility raised concerns over possible biopharmaceutical limitations. In order to improve their pharmaceutical potential we performed the biopharmaceutical profiling for nine pyrazole compounds using in vitro and computational methods. The experimental solubility was determined in five different media using a validated HPLC method. Although the experimental solubility was lower than the predicted one, a good linear relationship was observed. The results also indicated a minimal impact of endogenous tensioactives on solubility, suggesting dissolution rate limited absorption. The in silico experiments were focused on identification of molecular determinants of solubility, evaluation of drug-likeness, prediction of in vivo absorption based on mechanistic models, as well as identification of the main factors that could impact on the oral bioavailability. The results suggested that dose, solubility and particle size are the main determinants of absorption, whereas permeability has little effect, confirming the BCS Class II behavior of the compounds. The present investigation was able to rank the tested compounds in terms of biopharmaceutical behavior, and indicated the B3 series compounds as having a more favorable absorption profile making them the main candidates for advance to the pre-clinical in vivo studies.http://www.mdpi.com/1420-3049/19/10/16381acylthioureapyrazole derivativessolubilityFaSSIFFeSSIFADME prediction |
| spellingShingle | Valentina Anuta George Mihai Nitulescu Cristina Elena Dinu-Pîrvu Octavian Tudorel Olaru Biopharmaceutical Profiling of New Antitumor Pyrazole Derivatives Molecules acylthiourea pyrazole derivatives solubility FaSSIF FeSSIF ADME prediction |
| title | Biopharmaceutical Profiling of New Antitumor Pyrazole Derivatives |
| title_full | Biopharmaceutical Profiling of New Antitumor Pyrazole Derivatives |
| title_fullStr | Biopharmaceutical Profiling of New Antitumor Pyrazole Derivatives |
| title_full_unstemmed | Biopharmaceutical Profiling of New Antitumor Pyrazole Derivatives |
| title_short | Biopharmaceutical Profiling of New Antitumor Pyrazole Derivatives |
| title_sort | biopharmaceutical profiling of new antitumor pyrazole derivatives |
| topic | acylthiourea pyrazole derivatives solubility FaSSIF FeSSIF ADME prediction |
| url | http://www.mdpi.com/1420-3049/19/10/16381 |
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