Design, Synthesis and Pharmacological Evaluation of Benzoyl Hydrazone Derivative as Potential Multitarget Antidiabetic Agent: Molecular Docking, Biological Evaluation and ADME Profiling

Abstract

Diabetes is a chronic disease marked by increased blood glucose levels, often associated with oxidative stress, leading to severe complications. Current antidiabetic therapies often target single pathways, but a multitarget approach may enhance efficacy and reduce complications. Benzoyl hydrazone derivatives, known for diverse pharmacological activities, offer promise as multifunctional antidiabetic agents. The study focuses on the synthesis and biological evaluation of novel benzoyl hydrazone derivatives against three critical diabetic targets viz., aldose reductase, α-glucosidase and peroxisome proliferator-activated receptor-gamma (PPAR-γ). Eighteen derivatives were designed and subjected to molecular docking, with compound 4-hydroxy-3,5-dimethoxybenzaldehyde 4-hydroxybenzoylhydrazone) (HB18) exhibiting the strongest binding energies: –9.33 kcal/mol (aldose reductase), –6.34 kcal/mol (α-glucosidase) and –6.49 kcal/mol (PPAR-γ). ADME predictions indicated the favourable drug-like properties, high gastrointestinal absorption, compliance with Lipinski’s rule and low toxicity risk. Compound HB18 was synthesized with 80% yield and structurally confirmed by infrared R, nuclear magnetic resonance and mass spectroscopic analysis. Acute oral toxicity testing in rats (2000 mg/kg) revealed no mortality or adverse effects. In vitro antioxidant assays showed potent DPPH (IC₅₀ = 18.7 µg/mL) and scavenging of hydrogen peroxide activities in comparison to vitamin C. In vivo, compound HB18 significantly reduced fasting blood glucose from 126.21 to 287.62 mg/dL in streptozotocin-induced diabetic rats at 400 mg/kg (p < 0.01), with improved lipid profiles. This integrated in silico, in vitro and in vivo approach demonstrates compound HB18 as a promising multitarget antidiabetic candidate with antioxidant potential, warranting further pharmacological development.