Selective Binding of Cyclodextrins with Leflunomide and Its Pharmacologically Active Metabolite Teriflunomide

Abstract

The selectivity of encapsulation of leflunomide and teriflunomide by native α-, β- and γ-cyclodextrins was investigated through ¹H NMR and molecular modeling. Thermodynamic analysis revealed the main driving forces involved in the binding. For α-cyclodextrin, the partial encapsulation was obtained while deep penetration was characterized for the other two cyclodextrins, where the remaining polar fragment of the molecule is located outside the macrocyclic cavity. The interactions via hydrogen bonding are responsible for high negative enthalpy and entropy changes accompanying the complexation of cyclodextrins with teriflunomide. These results were in agreement with the molecular modeling calculations, which provide a clearer picture of the involved interactions at the atomic level.

Keywords: complex formation; cyclodextrin; leflunomide; molecular modeling; selectivity; teriflunomide.

Figure 1

Structural formulas of leflunomide (a) and teriflunomide (b).

Figure 2

2D ¹H NMR ROESY spectra of complexes of CDs with LEF and TEF.

Figure 2

2D ¹H NMR ROESY spectra of complexes of CDs with LEF and TEF.

Figure 3

Fragments of ¹H NMR spectra of CDs with and without TEF in phosphate buffer (pD 7.4) at 298.15 K.

Figure 3

Fragments of ¹H NMR spectra of CDs with and without TEF in phosphate buffer (pD 7.4) at 298.15 K.

Figure 4

Enthalpy–entropy compensation for complex formation of CDs with LEF and TEF at 298.15 K.

Figure 5

Docking results obtained for (A) α-CD/LEF, (B) α-CD/TEF, (C) β-CD/LEF, (D) β-CD/TEF, (E) γ-CD/LEF and (F) γ-CD/TEF. Cyclodextrin core is represented with thin lines and hydrogen bonds with yellow dashes.