Novel piperazine-pyridine conjugates as aldose reductase inhibitors: synthesis, DFT analysis, molecular docking, ADME evaluation, DPPH radical scavenging activity, and in vitro aldose reductase inhibitory activity.

Abstract

Introduction: Piperazine-pyridine-conjugated analogs were synthesized and evaluated for aldose reductase inhibition for treating diabetes mellitus.

Materials and methods: All synthesized compounds were structurally characterized by spectral studies. In addition, in silico ADME and cardiotoxicity predictions, molecular docking studies against aldose reductase (4JIR), and density functional theory (DFT) analysis were performed to evaluate the pharmacokinetic properties, binding interactions, and electronic characteristics of the synthesized compounds. The compounds were subsequently evaluated for DPPH Scavenging and aldose reductase inhibitory activity.

Results: Molecular docking revealed good binding affinity toward aldose reductase, with compound 7k showing the highest docking score and favorable hydrogen-bond and π-alkyl interactions. DFT analysis of compounds 7k and 7c indicated stable optimized structures, with 7k showing greater energetic stability, whereas 7c exhibited higher polarity and chemical reactivity. Compounds 7c (IC₅₀ = 8.5 ± 0.49 µM), 7h (IC₅₀ = 9.2 ± 0.71 µM), and 7k (IC₅₀ = 8.8 ± 0.29 µM) showed lower IC₅₀ values than the reference drug Sorbinil (IC₅₀ = 10.5 ± 0.44 µM) under the experimental conditions. Additionally, the synthesized compounds showed measurable DPPH radical scavenging activity, as a supportive assessment of antioxidant potential relevant to oxidative stress associated with diabetic complications.