Journal of Computer-Aided Molecular Design

, Volume 27, Issue 7, pp 615–635

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

DOI: 10.1007/s10822-013-9666-2

Cite this article as:
Karaman, R., Ghareeb, H., Dajani, K.K. et al. J Comput Aided Mol Des (2013) 27: 615. doi:10.1007/s10822-013-9666-2

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

https://static-content.springer.com/image/art%3A10.1007%2Fs10822-013-9666-2/MediaObjects/10822_2013_9666_Figa_HTML.gif

Keywords

Tranexamic acidProdrugsMenstrual bleedingFibrinolysisProton transferTraumatic haemorrhageHemophilia

Supplementary material

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

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