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

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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 pK a value of the catalyst. Substituted-pyridine derivatives with high pK a values were able to catalyze isomerization more efficiently than those with low pK a 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.

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

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Acknowledgments

The Karaman Co. and the German-Palestinian-Israeli fund agency are thanked for support of our computational facilities. Special thanks are also given to Angi Karaman, Donia Karaman, Rowan Karaman and Nardene Karaman for technical assistance.

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Authors and Affiliations

  1. Department of Bioorganic Chemistry, Faculty of Pharmacy, Al-Quds University, PO Box 20002, Jerusalem, Israel

    Rafik Karaman, Ghadeer Dokmak, Maryam Bader & Hussein Hallak

  2. Department of Chemistry and Chemical Technology, College of Science and Technology, Al-Quds University, Jerusalem, Israel

    Mustafa Khamis

  3. Department of Agriculture, Forestry and Environment, University of Basilicata, Potenza, 85100, Italy

    Laura Scrano & Sabino Aurelio Bufo

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  1. Rafik Karaman
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  2. Ghadeer Dokmak
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  4. Hussein Hallak
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  7. Sabino Aurelio Bufo
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Correspondence to Rafik Karaman.

Electronic supplementary materials

Xyz Cartesian coordinates for the calculated optimized structures for 1 Cis-6 Cis , 1TS1-6TS1, 1INT1 - 6INT1, 1TS2-6TS2, 1INT2-6INT2, 1TS3-6TS3, 1INT3-6INT3, 1P (Trans Drug )-6P (Trans Drug ). Table S1: Dft calculated properties for the moieties involved in the isomerization reactions of 1–6. Fig. S1a-1e: DFT optimized structures for 1TS1-6TS1, 1INT1-6INT1, 1INT2-6INT2, 1TS3-6TS3 and 1INT3-6INT3.

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Karaman, R., Dokmak, G., Bader, M. et al. Prodrugs of fumarate esters for the treatment of psoriasis and multiple sclerosis—a computational approach. J Mol Model 19, 439–452 (2013). https://doi.org/10.1007/s00894-012-1554-5

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  • DOI: https://doi.org/10.1007/s00894-012-1554-5

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