Integrated 3D-QSAR, molecular docking, molecular dynamics, DFT, in vitro, and in vivo evaluation of benzylidene-thiazolidinedione derivatives as aldose reductase inhibitors.

Abstract

Benzylidene-thiazolidinedione derivatives (SA01-SA12) were designed and synthesized using structure-based 3D-QSAR (R 2 = 0.845, Q 2 = 0.565) and pharmacophore modeling techniques to discover potent ALR2 inhibitors. Molecular docking analyses revealed that the selected compounds had notable binding affinities for ALR2, with SA02 achieving the most favourable MolDock score of -183.498 kcal mol-1, outperforming the reference drug epalrestat, which scored -157.994 kcal mol-1. Based on docking and drug-likeness screening results, twelve derivatives were synthesized and screened in vitro, revealing IC50 values ranging from 14.87 ± 2.06 to 59.35 ± 2.18 μM for goat lens aldose reductase and 60.107 ± 2.526 to 117.780 ± 2.089 nM for human aldose reductase, respectively. Compounds SA01 and SA02 showed significant inhibition of the human aldose reductase enzyme, with IC50 values of 65.361 ± 2.269 nM and 60.107 ± 2.526 nM, respectively, which are similar to epalrestat (IC50 = 52.154 ± 3.352 nM). Consistently, both SA01 and SA02 compounds also showed strong activity in the goat lens aldose reductase assay (IC50 = 15.37 and 14.87 μM, respectively). The synthesized compounds showed no significant cytotoxicity up to 10 μM in HepG2 cells. The overall stability of the complexes was supported by the analysis of RMSD, RMSF, PCA, FEL, DCCM, torsion profile, SASA, PSA, and secondary structure elements, which displayed conformational stability. The DFT of SA01 and SA02 showed higher HOMO-associated activity (-3.71 eV), and SA02 exhibited balanced HOMO (-3.52 eV) and LUMO (-6.02 eV) energies with an energy gap (ΔE = 3.52 eV), which suggested that SA02 displayed optimal stability and reactivity compared to epalrestat. For in vivo antidiabetic evaluation in STZ-nicotinamide-induced diabetic mice, SA02 at a dosage of 10 mg kg-1 exhibited the strongest antihyperglycemic effect, which was comparable to that of pioglitazone. SA02 showed enhanced levels of serum cholesterol, triglycerides, HDL, LDL, GLP-1, SGOT, and SGPT. The inflammatory profiles revealed that treatment with SA02 decreased the TNF-α and IL-1β levels in serum, liver, and kidney tissues, while IL-10 increased. Further haematological evaluation also demonstrated a protective effect against STZ-induced toxicity, with observed improvements in WBCs, neutrophils, lymphocytes, monocytes, RBCs, haemoglobin, haematocrit, and platelets. In summary, the research highlights SA02 as the most promising lead compound, with SA01 also showing significant ALR2 binding stability. This underscores the potential of benzylidene-thiazolidinedione derivatives as promising candidates for further exploration in combating diabetic complications.

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