Exploring the anti-diabetic potential of bis-Schiff bases of ibuprofen: insights into the in vitro, molecular docking and density functional theory analyses

Abstract

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia resulting from defects in insulin action or secretion. The synthesized bis-Schiff base derivatives of ibuprofen were evaluated for their in vitro α-amylase and α-glucosidase inhibitory activities using acarbose as a standard. Six compounds (13, 12, 14, 10, 9, and 11) exhibited superior dual inhibitory potency compared to acarbose, with IC₅₀ values ranging from 3.85 ± 0.05 µM to 14.47 ± 0.14 µM (α-amylase) and 4.36 ± 0.12 µM to 16.18 ± 0.12 µM (α-glucosidase), representing 1.1- to 4.2-fold enhanced activity. Compound 13 (3,4,5-trimethoxyphenyl) was the most potent, showing 4.2-fold (α-amylase) and 3.8-fold (α-glucosidase) improvement compared to acarbose. Molecular docking and DFT analyses revealed that compound 13's superior binding affinity (ΔG = −7.033 kcal mol⁻¹ vs. −5.868 kcal mol⁻¹ (acarbose)) arose from optimized π–π stacking with Trp59 and hydrogen bonding with Gln63/Ser108, facilitated by electron-donating methoxy groups. The FMO analysis showed a low HOMO–LUMO gap (ε = 1.840 eV) and a high electrophilicity index (ω = 2.094), correlating with enhanced charge-transfer interactions. Cytotoxicity assessments suggested no toxicity up to 1000 µg mL⁻¹. These findings position ibuprofen-based bis-Schiff bases as promising leads with enhanced potency and potentially improved drug-like properties compared to acarbose.