Synthesis of Thiazolidin-4-Ones Derivatives, Evaluation of Conformation in Solution, Theoretical Isomerization Reaction Paths and Discovery of Potential Biological Targets

Abstract

Thiazolin-4-ones and their derivatives represent important heterocyclic scaffolds with various applications in medicinal chemistry. For that reason, the synthesis of two 5-substituted thiazolidin-4-one derivatives was performed. Their structure assignment was conducted by NMR experiments (2D-COSY, 2D-NOESY, 2D-HSQC and 2D-HMBC) and conformational analysis was conducted through Density Functional Theory calculations and 2D-NOESY. Conformational analysis showed that these two molecules adopt exo conformation. Their global minimum structures have two double bonds (C=N, C=C) in Z conformation and the third double (C=N) in E. Our DFT results are in agreement with the 2D-NMR measurements. Furthermore, the reaction isomerization paths were studied via DFT to check the stability of the conformers. Finally, some potential targets were found through the SwissADME platform and docking experiments were performed. Both compounds bind strongly to five macromolecules (triazoloquinazolines, mglur3, Jak3, Danio rerio HDAC6 CD2, acetylcholinesterase) and via SwissADME it was found that these two molecules obey Lipinski's Rule of Five.

Keywords: DFT; NMR; drug-likeness; molecular docking; molecular dynamics; thazoline.

Scheme 1

Reagents and conditions: (i) thiosemicarbazide, EtOH, cat. AcOH, 80 °C, 4 h; (ii) methyl 2-chloroacetate, MeOH, CH₃COONa, 65 °C, 6 h; (iii) (a) benzaldehyde, MeOH, cat. Piperidine, 65 °C, 48 h (for DKI39) and (b) anisaldehyde cat. piperidine, rt, 7d (for DKI40).

Scheme 2

Structures of exo conformers of DKI39 (a) and DKI40 (b).

Scheme 3

Optimized conformations derived from DFT calculations for the DKI39 endo compound. In the Figure the dihedral angles rotated by 180° are shown. For instance, in DKI39en_1, the dihedral angle τ₁ was rotated and DKI39en_2 was obtained. In the orange circle, the double bond that indicates the endo nature of compound is shown.

Scheme 4

Optimized conformations derived from DFT calculations for the DKI40 endo compound. In the Figure, the dihedral angles rotated by 180° are shown. For instance, in DKI40en_1, the dihedral angle τ_3′ was rotated and DKI39en_2 was obtained. In the orange circle, the double bond that indicates the endo nature of compound is shown.

Scheme 5

The global minima conformations for (a) DKI39 and (b) DKI40 endo compounds.

Scheme 6

Optimized conformations derived from DFT calculations for DKI39 exo compound. In the Figure the dihedral angles rotated by 180° are shown. For instance, in DKI39ex_1, the dihedral angle τ₃ was rotated and DKI39ex_2 was obtained. In the orange circle, the double bond that indicates the exo nature of compound is shown.

Scheme 7

Optimized conformations derived from DFT calculations for the DKI40 exo compound. In the Figure, the dihedral angles rotated by 180° are shown. For instance, in DKI40ex_1, the dihedral angle τ_2′ was rotated and DKI40ex_2 was obtained. In the orange circle the double bond that indicates the exo nature of compound is shown.

Scheme 8

The lowest in energy conformations for (a) DKI39 and (b) DKI40 exo compounds.

Figure 1

NOE effects for DKI39 (top) and for DKI40 (bottom).

Figure 2

Schematic representation of the isomerization energy barrier between cis-trans for DKI39 (y = energy in kcal/mol, x = conformation).

Figure 3

Schematic representation of cis-trans kinetic isomerization for DKI39 exo compound (y = energy in kcal/mol, x = conformation). In each transition state, the dihedral angle, which is rotated by ~180°, is shown by an arrow.

Figure 4

Schematic representation of the isomerization energy barrier between cis −trans for DKI40 (y = energy in kcal/mol, x = conformation).

Figure 5

Schematic representation of cis-trans kinetic isomerization for DKI40 exo compound (y = Energy in kcal/mol, x = conformation). In each transition state, the dihedral angle, which is rotated by ~180°, is shown by arrow.

Figure 6

Binding mode of DKI39 (left, green color) with (a) triazoloquinazolines, (b) mglur3, (c) Jak3, (d) Danio rerio HDAC6 CD2 and (e) acetylcholinesterase. Binding modes of DKI40 (right, blue color) with (a) triazoloquinazolines, (b) mglur3, (c) Jak3, (d) Danio rerio HDAC6 CD2 and (e) acetylcholinesterase.

Figure 6

Binding mode of DKI39 (left, green color) with (a) triazoloquinazolines, (b) mglur3, (c) Jak3, (d) Danio rerio HDAC6 CD2 and (e) acetylcholinesterase. Binding modes of DKI40 (right, blue color) with (a) triazoloquinazolines, (b) mglur3, (c) Jak3, (d) Danio rerio HDAC6 CD2 and (e) acetylcholinesterase.

Figure 7

Comparison of binding free energies during repeated simulations (3 replicas) of DKI39 and DKI40 complexes in aqueous solution.

Scheme 9

Summary of the scientific work described in the manuscript.