Design, Synthesis, and In Vitro Kinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations
Based on DFT, MP2, and the density functional from Truhlar group (hybrid GGA: MPW1k) calculations for an acid-catalyzed hydrolysis of nine Kirby’s N-alkylmaleamic acids and two atenolol prodrugs were designed. The calculations demonstrated that the amide bond cleavage is due to intramolecular nucleo...
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| Format: | Article |
| Language: | English |
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Wiley
2014-01-01
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| Series: | The Scientific World Journal |
| Online Access: | http://dx.doi.org/10.1155/2014/248651 |
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| author | Rafik Karaman Alaa Qtait Khulod Khayyat Dajani Saleh Abu Lafi |
| author_facet | Rafik Karaman Alaa Qtait Khulod Khayyat Dajani Saleh Abu Lafi |
| author_sort | Rafik Karaman |
| collection | DOAJ |
| description | Based on DFT, MP2, and the density functional from Truhlar group (hybrid GGA: MPW1k) calculations for an acid-catalyzed hydrolysis of nine Kirby’s N-alkylmaleamic acids and two atenolol prodrugs were designed. The calculations demonstrated that the amide bond cleavage is due to intramolecular nucleophilic catalysis by the adjacent carboxylic acid group and the rate-limiting step is determined based on the nature of the amine leaving group. In addition, a linear correlation of the calculated and experimental rate values has drawn credible basis for designing atenolol prodrugs that are bitterless, are stable in neutral aqueous solutions, and have the potential to release the parent drug in a sustained release manner. For example, based on the calculated B3LYP/6-31 G (d,p) rates, the predicted t1/2 (a time needed for 50% of the prodrug to be converted into drug) values for atenolol prodrugs ProD 1-ProD 2 at pH 2 were 65.3 hours (6.3 hours as calculated by GGA: MPW1K) and 11.8 minutes, respectively. In vitro kinetic study of atenolol prodrug ProD 1 demonstrated that the t1/2 was largely affected by the pH of the medium. The determined t1/2 values in 1N HCl, buffer pH 2, and buffer pH 5 were 2.53, 3.82, and 133 hours, respectively. |
| format | Article |
| id | doaj-art-687b0117c1514513ab0782ffaca3f361 |
| institution | Kabale University |
| issn | 2356-6140 1537-744X |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | The Scientific World Journal |
| spelling | doaj-art-687b0117c1514513ab0782ffaca3f3612025-02-03T05:51:34ZengWileyThe Scientific World Journal2356-61401537-744X2014-01-01201410.1155/2014/248651248651Design, Synthesis, and In Vitro Kinetics Study of Atenolol Prodrugs for the Use in Aqueous FormulationsRafik Karaman0Alaa Qtait1Khulod Khayyat Dajani2Saleh Abu Lafi3Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, PalestineFaculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, PalestineFaculty of Public Health Sciences, Al-Quds University, P.O. Box 20002, Jerusalem, PalestineFaculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, PalestineBased on DFT, MP2, and the density functional from Truhlar group (hybrid GGA: MPW1k) calculations for an acid-catalyzed hydrolysis of nine Kirby’s N-alkylmaleamic acids and two atenolol prodrugs were designed. The calculations demonstrated that the amide bond cleavage is due to intramolecular nucleophilic catalysis by the adjacent carboxylic acid group and the rate-limiting step is determined based on the nature of the amine leaving group. In addition, a linear correlation of the calculated and experimental rate values has drawn credible basis for designing atenolol prodrugs that are bitterless, are stable in neutral aqueous solutions, and have the potential to release the parent drug in a sustained release manner. For example, based on the calculated B3LYP/6-31 G (d,p) rates, the predicted t1/2 (a time needed for 50% of the prodrug to be converted into drug) values for atenolol prodrugs ProD 1-ProD 2 at pH 2 were 65.3 hours (6.3 hours as calculated by GGA: MPW1K) and 11.8 minutes, respectively. In vitro kinetic study of atenolol prodrug ProD 1 demonstrated that the t1/2 was largely affected by the pH of the medium. The determined t1/2 values in 1N HCl, buffer pH 2, and buffer pH 5 were 2.53, 3.82, and 133 hours, respectively.http://dx.doi.org/10.1155/2014/248651 |
| spellingShingle | Rafik Karaman Alaa Qtait Khulod Khayyat Dajani Saleh Abu Lafi Design, Synthesis, and In Vitro Kinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations The Scientific World Journal |
| title | Design, Synthesis, and In Vitro Kinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations |
| title_full | Design, Synthesis, and In Vitro Kinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations |
| title_fullStr | Design, Synthesis, and In Vitro Kinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations |
| title_full_unstemmed | Design, Synthesis, and In Vitro Kinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations |
| title_short | Design, Synthesis, and In Vitro Kinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations |
| title_sort | design synthesis and in vitro kinetics study of atenolol prodrugs for the use in aqueous formulations |
| url | http://dx.doi.org/10.1155/2014/248651 |
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