Discovery of Hydrazine Clubbed Thiazoles as Potential Antidiabetic Agents: Synthesis, Biological Evaluation, and Molecular Docking Studies

Abstract

In this study, hydrazine clubbed thiazole derivatives (3a-3j) were obtained by Hantzsch thiazole synthesis and characterized by MS, ¹H NMR, and ¹³C NMR. The inhibitory potentials of the derivatives against diabetes-related enzymes such as aldose reductase (AR), α-glycosidase (α-GLY), and α-amylase (α-AMY) were experimentally determined, and the results were supported by molecular docking. The results showed that the derivatives (3a-3j) displayed varied degree of potential inhibitory activity, with K_I values covering the following ranges: 5.47 ± 0.53 to 23.89 ± 1.46 nM for AR and 1.76 ± 0.01 to 24.81 ± 0.15 μM for α-GLY, and with IC₅₀ values 4.94-28.17 μM for α-AMY, as compared to standard epalrestat and acarbose (K_I: 34.53 ± 2.52 nM for AR and 23.53 ± 2.72 μM for α-GLY, respectively). The selective activity of these derivatives on antidiabetic enzymes may be important for the treatment of diabetes and may lead to the development of alternative new compounds for this purpose.

Keywords: ADME; aldose reductase; alpha‐amylase; alpha‐glucosidase; antidiabetic; molecular docking; thiazole.

Figure 1

Some examples of hydrazine clubbed thiazoles as α‐GLY and α‐AMY inhibitors.

Scheme 1

The synthetic pathway of the compounds (3a–3j). Reagents and conditions; i : K₂CO₃, DMF, reflux, 24 h, ii : thiosemicarbazide, acetic acid, EtOH, reflux, 24 h, iii : EtOH, reflux, 12 h.

Figure 2

SAR studies of the compounds 3a–3j for AR, α‐GLY, and α‐AMY inhibitory activity.

Figure 3

Protein–ligand interaction 2D (A) and 3D (B) (α‐AMY, represented by 2QMK, was subjected to molecular docking studies with compound 3g. α‐GLY, represented by 3A4A, was subjected to molecular docking studies with compound 3c. The AR represented by 4JIR was subjected to molecular docking studies with compound 3c). Binding mode and visual interaction (H‐bonds (C), Aromatic (D), and Hydrophobicity (E)) of designed 3c and 3g against 2QMK, 3A4A, and 4JIR.

Figure 4

Protein–ligand interaction 2D (A) and 3D (B) of standard drug (epalrestat and acarbose) against 2QMK, 3A4A, and 4JIR. Binding mode and visual interaction (H‐bonds (C), Aromatic (D), and Hydrophobicity (E) of standard drug (epalrestat and acarbose) against 2QMK, 3A4A, and 4JIR.

Figure 5

BOILED‐Egg plot for the synthesized compounds (3c and 3g).