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. 2024;16(22):2395-2410.
doi: 10.1080/17568919.2024.2401314. Epub 2024 Oct 11.

Potent α-glucosidase inhibitors with benzimidazole-propionitrile hybridization; synthesis, bioassay and docking study

Ebrahim Saeedian Moghadam  1 , Abdullah Mohammed Al-Sadi  2 , Mahdis Sadeghi Moghadam  3 , Bahareh Bayati  3 , Somayeh Mojtabavi  4 , Mohammad Ali Faramarzi  4 , Mohsen Amini  1   3 , Raid Abdel-Jalil  5
Affiliations

Potent α-glucosidase inhibitors with benzimidazole-propionitrile hybridization; synthesis, bioassay and docking study

Ebrahim Saeedian Moghadam et al. Future Med Chem. 2024.

Abstract

Background: Diabetes is characterized by a lack of insulin and insensitivity to insulin. In 2013, the global diabetes population was 382 million, with 90% of them having type 2 diabetes (non-insulin-dependent). It is predicted that this number will increase to 592 million by 2035.Aim: Here, we aimed to synthesize a series of benzimidazole-based derivatives B1-B32 with α-glucosidase inhibition potential as antidiabetic agents.Methods: Compounds B1-B32 were prepared in three three-step reactions, and the structures were elucidated using spectroscopic methods, namely 1H NMR, 13C NMR, MS and IR. Enzyme inhibition and kinetic study were done using commercial assay kits, and molecular docking study using autodock4.Results: Bioassay data showed that twenty-four out of the thirty-two tested compounds exhibited IC50 values ranging from 44 to 745 μM, surpassing the standard molecule, acarbose (IC50: 750 μM). it was determined that the best compound, B10, functions as a competitive inhibitor. Additionally, a molecular docking study provided insights into the interactions between the four most promising compounds (B5, B6, B10 and B28) and the active site residues within the enzyme.Conclusion: The tested compounds are interesting α-glucosidase inhibitors, which indicates the benefit of more bioassay studies, especially in vivo studies.

Keywords: ADMET; benzimidazole; diabetes mellitus; molecular docking; nitrile; α-glucosidase.

Plain language summary

[Box: see text].

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Conflict of interest statement

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
(A) Common α-glucosidase inhibitors. (B) Reported benzimidazole-based structures with α-glucosidase inhibitory effect. (C) Reported α-glucosidase inhibitor structures containing nitrile moiety. (D) Designed structure in current work.
Figure 2.
Figure 2.
Synthetic pathway to obtain target compounds B1-B32.
Figure 3.
Figure 3.
SAR study related to synthesized structures with (A) ortho-substituted benzaldehydes, (B) meta-substituted benzaldehydes, (C) para-substituted benzaldehydes, (D) poly fluoro-substituted benzaldehydes, (E) dichloro-substituted benzaldehydes.
Figure 4.
Figure 4.
Kinetics of α-glucosidase inhibition by sample B10. (A) The Lineweaver–Burk plot in the absence and presence of different concentrations of the sample B10; (B) The secondary plot between Km and various concentrations of the sample B10.
Figure 5.
Figure 5.
2D and 3D visualization of the interactions of compounds B5, B6, B10 and B28 in the active site of α-glucosidase enzyme (PDB ID: 3A4A). (A) interactions of compound B5, (B) interactions of compound B6, (C) interactions of compound B10, (D) interactions of compound B28. (E) 2D visualization of interactions of acarbose in the active site of α-glucosidase enzyme (PDB ID: 3A4A). (F) Superimposition of compounds B5, B6, B10 and B28 with acar.
See this image and copyright information in PMC

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