Journal of Molecular Modeling

, Volume 19, Issue 1, pp 439–452 | Cite as

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

  • Rafik Karaman
  • Ghadeer Dokmak
  • Maryam Bader
  • Hussein Hallak
  • Mustafa Khamis
  • Laura Scrano
  • Sabino Aurelio Bufo
Original Paper

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.

Figure

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

Keywords

Prodrug Psoriasis Multiple sclerosis Monomethylmaleate Isomerization of monomethylmaleate DFT calculation Pyridine-catalyzed cis-trans isomerization 

Supplementary material

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

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Rafik Karaman
    • 1
  • Ghadeer Dokmak
    • 1
  • Maryam Bader
    • 1
  • Hussein Hallak
    • 1
  • Mustafa Khamis
    • 2
  • Laura Scrano
    • 3
  • Sabino Aurelio Bufo
    • 3
  1. 1.Department of Bioorganic Chemistry, Faculty of PharmacyAl-Quds UniversityJerusalemIsrael
  2. 2.Department of Chemistry and Chemical Technology, College of Science and TechnologyAl-Quds UniversityJerusalemIsrael
  3. 3.Department of Agriculture, Forestry and EnvironmentUniversity of BasilicataPotenzaItaly

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