Design, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditions
| dc.contributor.author | Karaman, Rafik | |
| dc.contributor.author | Ghareeb, Hiba | |
| dc.contributor.author | Dajani, Khuloud Kamal | |
| dc.contributor.author | Hallak, Hussein | |
| dc.date.accessioned | 2018-09-25T17:31:54Z | |
| dc.date.available | 2018-09-25T17:31:54Z | |
| dc.date.issued | 2013-07-13 | |
| dc.description.abstract | Based on density functional theory (DFT) calculations for the acid-catalyzed hydrolysis of several maleamic acid amide derivatives four tranexamic acid prodrugs were designed. The DFT results on the acid catalyzed hydrolysis revealed that the reaction rate-limiting step is determined on the nature of the amine leaving group. When the amine leaving group was a primary amine or tranexamic acid moiety, the tetrahedral intermediate collapse was the rate-limiting step, whereas in the cases by which the amine leaving group was aciclovir or cefuroxime the rate-limiting step was the tetrahedral intermediate formation. The linear correlation between the calculated DFT and experimental rates for N-methylmaleamic acids 1–7 provided a credible basis for designing tranexamic acid prodrugs that have the potential to release the parent drug in a sustained release fashion. For example, based on the calculated B3LYP/6-31G(d,p) rates the predicted t1/2 (a time needed for 50 % of the prodrug to be converted into drug) values for tranexamic acid prodrugs ProD 1–ProD 4 at pH 2 were 556 h [50.5 h as calculated by B3LYP/ 311?G(d,p)] and 6.2 h as calculated by GGA: MPW1K), 253 h, 70 s and 1.7 h, respectively. Kinetic study on the interconversion of the newly synthesized tranexamic acid prodrug ProD 1 revealed that the t1/2 for its conversion to the parent drug was largely affected by the pH of the medium. The experimental t1/2 values in 1 N HCl, buffer pH 2 and buffer pH 5 were 54 min, 23.9 and 270 h, respectively. | en_US |
| dc.identifier.issn | 1573-4951 | |
| dc.identifier.uri | https://dspace.alquds.edu/handle/20.500.12213/994 | |
| dc.language.iso | en_US | en_US |
| dc.publisher | Springer Science+Business Media Dordrecht | en_US |
| dc.subject | Tranexamic acid | en_US |
| dc.subject | Prodrugs | en_US |
| dc.subject | Menstrual | en_US |
| dc.subject | bleeding | en_US |
| dc.subject | Fibrinolysis | en_US |
| dc.subject | Proton transfer | en_US |
| dc.subject | Traumatic | en_US |
| dc.subject | haemorrhage | en_US |
| dc.subject | Hemophilia | en_US |
| dc.title | Design, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditions | en_US |
| dc.type | Article | en_US |