Prodrugs of fumarate esters for the treatment of psoriasis and multiple sclerosis—a computational approach Karaman, Rafik Dokmak, Ghadeer Bader, Maryam Hallak, Hussein Khamis, Mustafa 2018-09-04T09:51:08Z 2018-09-04T09:51:08Z 2012-09-02
dc.description.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. en_US
dc.identifier.issn 0948-5023
dc.language.iso en_US en_US
dc.publisher Springer-Verlag 2012 en_US
dc.subject Prodrug en_US
dc.subject Psoriasis en_US
dc.subject Multiple sclerosis en_US
dc.subject Monomethylmaleate en_US
dc.subject Isomerization ofmonomethylmaleate en_US
dc.subject DFTcalculation en_US
dc.subject Pyridine-catalyzed cis-trans isomerization en_US
dc.title Prodrugs of fumarate esters for the treatment of psoriasis and multiple sclerosis—a computational approach en_US
dc.type Article en_US
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