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dc.contributor.authorKaraman, Rafik
dc.contributor.authorGhareeb, Hiba
dc.contributor.authorDajani, Khuloud Kamal
dc.contributor.authorHallak, Hussein
dc.date.accessioned2018-09-25T17:31:54Z
dc.date.available2018-09-25T17:31:54Z
dc.date.issued2013-07-13
dc.identifier.issn1573-4951
dc.identifier.urihttps://dspace.alquds.edu/handle/20.500.12213/994
dc.description.abstractBased 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.language.isoen_USen_US
dc.publisherSpringer Science+Business Media Dordrechten_US
dc.subjectTranexamic aciden_US
dc.subjectProdrugsen_US
dc.subjectMenstrualen_US
dc.subjectbleedingen_US
dc.subjectFibrinolysisen_US
dc.subjectProton transferen_US
dc.subjectTraumaticen_US
dc.subjecthaemorrhageen_US
dc.subjectHemophiliaen_US
dc.titleDesign, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditionsen_US
dc.typeArticleen_US


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