Designing Potent α-Glucosidase Inhibitors: A Synthesis and QSAR Modeling Approach for Biscoumarin Derivatives

Abstract

Nineteen biscoumarins were synthesized, well-characterized, and evaluated against α-glucosidases in vitro. Of these, six compounds (10, 12, 16, and 17–19) were newly synthesized and not previously reported in the chemical literature. The majority of the synthesized derivatives demonstrated significant inhibitory activity. A quantitative structure–activity relationship (QSAR) model was developed, revealing a strong correlation between the anti-α-glucosidase activity and selected molecular descriptors. Based on this model, two new compounds (18 and 19) were designed, which exhibited the strongest inhibition with IC50 values of 0.62 and 1.21 μM, respectively, when compared to the positive control (acarbose) with an IC50 value of 93.63 μM. Enzyme kinetic studies of compounds 18 and 19 revealed their competitive inhibition with K i values of 3.93 and 1.80 μM, respectively. Computational studies demonstrated that compound 18 could be inserted into the original binding site (OBS) of α-glucosidase MAL12 and form multiple hydrophobic interactions with nearby amino acids, with the bromo group playing an essential role in enhancing the binding strength and stability at the OBS of the enzyme based on the quantum mechanical calculations using the fragment molecular orbital method. These findings provide valuable insights into the design of potent α-glucosidase inhibitors, which may have potential therapeutic applications in the treatment of diabetes and related diseases.

Unlocking E‐arylidene Steroid Derivatives as Promising α‐Glucosidase Inhibitors

“…This enhanced binding energy of 5 d can be attributed to its predominant hydrophobic interactions, which play a key role in stabilizing the ligand within the binding pocket. In contrast, acarbose predominantly formed hydrogen bond interactions with nearby residues in this pocket, a finding consistent with related research [25] (Figure 7). [23a]…”

“…This binding mode is consistent with previous findings. [25][26] In contrast, compound 5 d interacted with the maltose binding site through its acetyl group, as illustrated in Figure 6. Importantly, compound 5 d exhibited a superior binding interaction energy compared to acarbose, indicating its poten-tial as a more effective inhibitor at the OBS site (Table 4).…”

“…[31] The 3D structures of selected E-arylidene steroid and its derivatives were prepared on GaussView 6.0.16 and optimized by gaussian16 using B3LYP/6-31G + (d,p) basis set. [25,32] For the molecular docking study, AutoDock Vina 1.1.2 [24] was utilized. Both protein and ligand structures were charged and converted to PDBQT format using AutoDockTools.…”

Unsymmetrical Bis‐Coumarin Based on o‐Hydroxy Aldehydes and 4‐Hydroxy Coumarin: Expedient Synthesis, Single Crystal X‐rays and DFT Studies

“…They have shown lot of biological applications [8] and some of the derivatives of bis‐coumarin have been extensively studied as analytes [9] . Recent research [10–13] also emerges the significant importance of the bis‐coumarin type compounds in various occasions. Most of the reported methods rely on the involvement of a three component condensation of 4‐hydroxy coumarin ( 1 ) units and an aldehyde ( 2 ) through Knoevenagel condensation followed by Michael addition in the presence of various catalysts under room temperature or elevated temperature [5b,6b,15] .…”