Journal of Computer-Aided Molecular Design

, Volume 27, Issue 7, pp 615–635 | Cite as

Design, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditions

  • Rafik Karaman
  • Hiba Ghareeb
  • Khuloud Kamal Dajani
  • Laura Scrano
  • Hussein Hallak
  • Saleh Abu-Lafi
  • Gennaro Mecca
  • Sabino A. Bufo
Article

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 17 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 1ProD 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.

Graphical Abstract

Keywords

Tranexamic acid Prodrugs Menstrual bleeding Fibrinolysis Proton transfer Traumatic haemorrhage Hemophilia 

Notes

Acknowledgments

The author would like to acknowledge funding by the German Research Foundation (DFG, ME 1024/8-1) and Exo Research Organization, Potenza, Italy. Special thanks are also given to Nardene Karaman, Angi Karaman, Donia Karaman, and Rowan Karaman for technical assistance.

Supplementary material

10822_2013_9666_MOESM1_ESM.doc (260 kb)
Supplementary material 1 (DOC 260 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Rafik Karaman
    • 1
    • 3
  • Hiba Ghareeb
    • 1
  • Khuloud Kamal Dajani
    • 2
  • Laura Scrano
    • 3
  • Hussein Hallak
    • 1
  • Saleh Abu-Lafi
    • 1
  • Gennaro Mecca
    • 4
  • Sabino A. Bufo
    • 3
  1. 1.Bioorganic Chemistry Department, Faculty of PharmacyAl-Quds UniversityJerusalemIsrael
  2. 2.Faculty of Public Health SciencesAl-Quds UniversityJerusalemIsrael
  3. 3.Department of SciencesUniversity of BasilicataPotenzaItaly
  4. 4.Exo Research OrganizationPotenzaItaly

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