Prodrugs of fumarate esters for the treatment of psoriasis and multiple sclerosis—a computational approach
Date
2012-09-02
Authors
Karaman, Rafik
Dokmak, Ghadeer
Bader, Maryam
Hallak, Hussein
Khamis, Mustafa
Journal Title
Journal ISSN
Volume Title
Publisher
Springer-Verlag 2012
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 C0C 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. Substitutedpyridine
derivatives with high pKa values were able to catalyze
isomerization more efficiently than those with low pKa
values. The calculated relative rates for prodrugs 1–6
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 3–5 are expected to be slow and that of prodrugs 2 and 6 are expected to be relatively fast. Hence,
prodrugs 2 and 3–5 have the potential to be utilized as prodrugs
for the slow release of monomethylfumarate in the
treatment of psoriasis and multiple sclerosis.
Description
Keywords
Prodrug , Psoriasis , Multiple sclerosis , Monomethylmaleate , Isomerization ofmonomethylmaleate , DFTcalculation , Pyridine-catalyzed cis-trans isomerization