Potential of imidazole derivatives in reducing vascular complications in experimental diabetes

Diabetes-induced endothelial dysfunction significantly contributes to cardiovascular complications, yet there is a limited availability of effective targeted therapies. This study assessed two novel imidazole derivatives, DMB-PTCI and ADBPI, through an integrated multiscale approach that includes quantum chemical analysis, in vivo validation, and computational modelling. Density functional theory revealed that DMB-PTCI exhibits a narrower HOMO-LUMO gap (2.96 vs. 3.91 eV), higher electrophilicity (1.88 vs. 1.25 eV), and greater softness (0.18 vs. 0.16 eV⁻¹) compared to ADBPI, indicating enhanced reactivity. In streptozotocin-induced diabetic rats, DMB-PTCI and ADBPI significantly reduced fasting blood glucose levels from 285.0 ± 15.5 mg/dL to 121.2 ± 6.7 mg/dL and 148.7 ± 6.5 mg/dL, respectively. Additionally, these treatments restored insulin levels from 3.9 ± 0.4 µIU/mL to 9.9 ± 0.4 µIU/mL and 9.2 ± 0.3 µIU/mL. Both compounds demonstrated improvements in lipid profiles, oxidative stress, inflammation, and endothelial biomarkers. Notably, DMB-PTCI exhibited stronger effects, as indicated by lower malondialdehyde levels (53.3 ± 1.9 nmol/g tissue) and higher nitric oxide levels (28.7 ± 0.7 nmol/g tissue). Molecular docking studies on human lysosomal acid-α-glucosidase revealed that DMB-PTCI binds more strongly (-8.455 kcal/mol) than ADBPI (-7.590 kcal/mol) and the reference ligand (-5.102 kcal/mol). This finding is further supported by MM-PBSA binding free energy calculations, which yielded a value of -11.60 ± 8.66 kcal/mol. Additionally, ADMET analysis indicated a prolonged half-life for DMB-PTCI (108.60 h), while ADBPI demonstrated higher oral bioavailability (0.97). Overall, DMB-PTCI consistently demonstrated superior performance across theoretical, experimental, and computational evaluations. This highlights its potential as a leading candidate for managing diabetes-associated endothelial dysfunction and suggests the need for further preclinical investigation.ADMET profiling revealed safety concerns, including the risk of hepatotoxicity and poor solubility associated with DMB-PTCI, indicating the need for further structural optimization and preclinical validation prior to clinical translation.