Journal of Molecular Modeling

, Volume 19, Issue 1, pp 439–452

Prodrugs of fumarate esters for the treatment of psoriasis and multiple sclerosis—a computational approach

Authors

    • Department of Bioorganic Chemistry, Faculty of PharmacyAl-Quds University
  • Ghadeer Dokmak
    • Department of Bioorganic Chemistry, Faculty of PharmacyAl-Quds University
  • Maryam Bader
    • Department of Bioorganic Chemistry, Faculty of PharmacyAl-Quds University
  • Hussein Hallak
    • Department of Bioorganic Chemistry, Faculty of PharmacyAl-Quds University
  • Mustafa Khamis
    • Department of Chemistry and Chemical Technology, College of Science and TechnologyAl-Quds University
  • Laura Scrano
    • Department of Agriculture, Forestry and EnvironmentUniversity of Basilicata
  • Sabino Aurelio Bufo
    • Department of Agriculture, Forestry and EnvironmentUniversity of Basilicata
Original Paper

DOI: 10.1007/s00894-012-1554-5

Cite this article as:
Karaman, R., Dokmak, G., Bader, M. et al. J Mol Model (2013) 19: 439. doi:10.1007/s00894-012-1554-5

Abstract

Density functional theory (DFT) calculations at B3LYP/6-31 G (d,p) and B3LYP/6-311 + G(d,p) levels for the substituted pyridine-catalyzed isomerization of monomethyl maleate revealed that isomerization proceeds via four steps, with the rate-limiting step being proton transfer from the substituted pyridinium ion to the C=C double bond in INT1. In addition, it was found that the isomerization rate (maleate to fumarate) is solvent dependent. Polar solvents, such as water, tend to accelerate the isomerization rate, whereas apolar solvents, such as chloroform, act to slow down the reaction. A linear correlation was obtained between the isomerization activation energy and the dielectric constant of the solvent. Furthermore, linearity was achieved when the activation energy was plotted against the pKa value of the catalyst. Substituted-pyridine derivatives with high pKa values were able to catalyze isomerization more efficiently than those with low pKa values. The calculated relative rates for prodrugs 16 were: 1 (406.7), 2 (7.6 × 106), 3 (1.0), 4 (20.7), 5 (13.5) and 6 (2.2 × 103). This result indicates that isomerizations of prodrugs 1 and 35 are expected to be slow and that of prodrugs 2 and 6 are expected to be relatively fast. Hence, prodrugs 2 and 35 have the potential to be utilized as prodrugs for the slow release of monomethylfumarate in the treatment of psoriasis and multiple sclerosis.

https://static-content.springer.com/image/art%3A10.1007%2Fs00894-012-1554-5/MediaObjects/894_2012_1554_Figa_HTML.gif
Figure

Substituted pyridine-catalyzed isomerization of monomethylmaleate (prodrug, cis-isomer) to monomethylfumerate (parental drug, trans-isomer)

Keywords

ProdrugPsoriasisMultiple sclerosisMonomethylmaleateIsomerization of monomethylmaleateDFT calculationPyridine-catalyzed cis-trans isomerization

Supplementary material

894_2012_1554_MOESM1_ESM.doc (1.3 mb)
ESM 1(DOC 1374 kb)

Copyright information

© Springer-Verlag 2012