title: Design, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditions.
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.
authors.affiliation: Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University, Jerusalem, Israel. dr_karaman@yahoo.com
authors.forename: Rafik
authors.initials: R
authors.lastname: Karaman
authors.forename: Hiba
authors.initials: H
authors.lastname: Ghareeb
authors.forename: Khuloud Kamal
authors.initials: KK
authors.lastname: Dajani
authors.forename: Laura
authors.initials: L
authors.lastname: Scrano
authors.forename: Hussein
authors.initials: H
authors.lastname: Hallak
authors.forename: Saleh
authors.initials: S
authors.lastname: Abu-Lafi
authors.forename: Gennaro
authors.initials: G
authors.lastname: Mecca
authors.forename: Sabino A
authors.initials: SA
authors.lastname: Bufo
mesh_terms: D015195:Drug Design; D006470:Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014148:Tranexamic Acid / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: D011355:Prodrugs; D014148:Tranexamic Acid