Dual α-amylase and α-glucosidase inhibition by 1,2,4-triazole derivatives for diabetes treatment

Abstract

The development of effective antidiabetic agents remains a critical challenge in diabetes management. In this study, we introduce novel 1,2,4-triazole-based derivatives designed as dual inhibitors of α-amylase and α-glucosidase, key enzymes in carbohydrate metabolism. Molecular docking identified six promising candidates, with compounds 4 and 10 showing the highest potency. Both compounds exhibited strong α-glucosidase inhibition (IC₅₀ = 0.27 ± 0.01 µg/mL and 0.31 ± 0.01 μg/mL, respectively), surpassing acarbose, and also demonstrated potent α-amylase inhibition (IC₅₀ = 0.19 ± 0.01 μg/mL and 0.26 ± 0.01 μg/mL, respectively). Structure-activity relationship analysis highlighted the crucial role of acetyl and bromo substituents in enhancing enzyme inhibition. These findings position triazole-based scaffolds as promising candidates for the development of next-generation antidiabetic therapies.

Keywords: 1,2,4-Triazole derivatives; Anti-diabetic activity; In vitro enzyme inhibition; Molecular docking analysis; α-Amylase inhibitors; α-Glucosidase inhibitors.

Fig. 1

Acarbose, miglitol, voglibose, and some FDA approved bioactive agents containing 1,2,4-triazole ring structure.

Fig. 2

Structures of α-amylase and/or α-glucosidase inhibitors containing 1,2,4-triazole nucleus (I, II, III), α-glucosidase inhibitors containing thioacetamide linker (IV, V, VI) structures, and optimization strategy of designed molecules.

Fig. 3

Rational of the work.

Scheme 1

Pathway to the target 1,2,4-triazole new substances containing thioacetamide (1–10). Reagents and conditions: (I) Phenyl isothiocyanate, EtOH, reflux; (II) 10% NaOH, reflux; (III) HCl, r. t; (IV) 2-Chloroacetyl chloride, acetic acid, r. t; (V) Substituted 2-chloro-N-phenylacetamide, NaOH, EtOH, reflux for compounds (1–7) and (9–10); (VI) Substituted 2-chloro-N-phenylacetamide, triethylamine, EtOH, r. t. for compound 8.

Fig. 4

Summarized SAR of the produced 1,2,4-triazole containing thioacetamide.

Fig. 5

Two- and three-dimensional representations for enzyme α-amylase (PDB ID: 2QV4) for forxiga and acarbose.

Fig. 6

Two- and three-dimensional representations for enzyme α-amylase (PDB ID: 2QV4).

Fig. 7

Two- and three-dimensional representations for enzyme α-glucosidase (PDB ID: 3AJ7) for forxiga and acarbose.

Fig. 8

Two- and three-dimensional representations for enzyme α-glucosidase (PDB ID: 3AJ7).

Fig. 9

α-amylase activity of derivatives 3, 4, 6, 8, 9, and 10 compared to acarbose.

Fig. 10

α-Glucosidase activity of derivatives 3, 4, 6, 8, 9, and 10 compared to acarbose.

Fig. 11

(a) Plot of protein backbone RMSD against time; (b) RMS fluctuation; (c) solvent-accessible surface area; (d) radius of gyration; (e) volume; and (f) density analysis for the complexes 3AJ7: compound 10 (pink) and 3AJ7: compound 4 (cyan).

Fig. 12

(a) Plot of protein backbone RMSD against time; (b) RMS fluctuation; (c) solvent-accessible surface area; (d) radius of gyration; (e) volume; and (f) density analysis for the complexes 2QV4: compound 10 (orange) and 2QV4: compound 4 (green).