Prodrugs of fumarate esters for the treatment of psoriasis and multiple sclerosis (MS) - A computational approach

DFT at B3LYP/6-31G (d,p) and B3LYP/6-311 + G(d,p) levels calculations for the substituted pyridine- catalyzed isomerization of monomethyl maleate revealed that the reaction proceeds via four steps where the step by which a proton is transferred from the substituted pyridinium ion into the C-C double bond in INT1 (step 2 in Scheme 2) is the rate limiting step. 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, otherwise apolar solvents, such as chloroform, act slowing down the reaction. A linear correlation was obtained between the isomerization activation energy and the dielectric constant of the solvent. Furthermore, a linearity was achieved when the activation energy was plotted against the pka value of the catalyst. Substituted-pyridine derivatives having high pka values are able to catalyze the isomerization more efficiently than those having low pka values.