Exploring the anti-diabetic potential of bis-Schiff base derivatives of benzimidazole: In-Vitro α-amylase, α-glucosidase inhibition, molecular docking, ADMET and DFT studies

May 7, 2025Computational biology and chemistry

Anti-diabetic potential of bis-Schiff base benzimidazole compounds through enzyme inhibition and computer simulations

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Abstract

Seven synthesized benzimidazole based bis-Schiff base derivatives showed strong anti-diabetic potential with IC values ranging from 2.84 ± 0.12 to 16.70 ± 1.23 µM.

The compounds exhibited varying inhibitory activities against α-amylase and α-glucosidase.
Compound 2g demonstrated the strongest binding affinity and inhibition at IC= 6.94 ± 0.07 μM.
The docking study indicated a correlation between binding affinity and α-glucosidase inhibitory activity.
The predicted ADMET profile raised concerns about absorption, potential toxicity, and drug development challenges.
Structural features, such as intramolecular hydrogen bonding and molecular reactivity, may influence inhibitory activity.

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This work explores the anti-diabetic activities of some synthesized benzimidazole based bis-Schiff base derivatives. The synthesized products were screened for their in vitro α-amylase and α-glucosidase inhibitory activities. In the synthetic derivatives, seven compounds attributed excellent anti-diabetic potential in the range of ICvalues from (IC= 2.84 ± 0.12 and 3.16 ± 0.05 µM) to (IC= 15.83 ± 1.11 and 16.70 ± 1.23 µM), while the remaining derivatives were found significant to less active when compared with the standard acarbose. The docking study correlates well with the α-glucosidase inhibitory activity, particularly for compounds 2 g and 2k, which showing strong binding affinity and hydrogen bonding. Compound 2 g, with the strongest binding affinity, also demonstrates potent inhibition (IC= 6.94 ± 0.07 μM). The synthesized compounds exhibit promising inhibitory activity against α-amylase and α-glucosidase, but their predicted ADMET profile presents significant challenges for their development as oral drugs. The poor absorption, high PPB, potential for CYP inhibition, and moderate toxicity risks highlight the need for further structural optimization. The frontier molecular orbitals (FMOs) analysis provides the LUMO delocalized on the benzylidene ring, influenced by the substitution pattern, appears to be a key factor influencing inhibitory activity. The higher reactivity (smaller energy gap) observed for some compounds, particularly 2k, might contribute to their enhanced activity. The molecular topology of the synthesized bis-Schiff bases showed a strong intramolecular hydrogen bond between the hydroxyl group at the 2-position of the benzylidene ring and the carbonyl oxygen of the linker. These interactions could pre-organize the molecule for better binding to the enzyme. 50 50 50 50

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Exploring the anti-diabetic potential of bis-Schiff base derivatives of benzimidazole: In-Vitro α-amylase, α-glucosidase inhibition, molecular docking, ADMET and DFT studies

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