Exploration of Antidiabetic Activity in Novel Benzimidazole Schiff Bases: Design, Synthesis, and Biological Evaluation

The escalating global prevalence of diabetes mellitus necessitates the development of novel therapeutic agents with enhanced efficacy and improved safety profiles. This study presents the rational design, synthesis, and comprehensive biological evaluation of a series of benzimidazole-based Schiff base derivatives as potential antidiabetic agents. Benzimidazole scaffolds have demonstrated significant pharmacological versatility, while Schiff bases are recognized for their diverse biological activities and structural flexibility. The strategic combination of these pharmacophores was hypothesized to yield compounds with superior antidiabetic properties. A series of novel benzimidazole Schiff base derivatives were synthesized through conventional condensation reactions followed by microwave assisted synthesis between substituted benzimidazole amine and various aromatic aldehyde. The structures of synthesized compounds were confirmed using spectroscopic techniques including ¹H NMR, ¹³C NMR, IR, and mass spectrometry. Molecular docking studies were performed to elucidate potential binding interactions with key diabetic targets. Auto Dock Tools 1.5.4 (ADT) was utilized for preparing the docking input files. Docking studies specifically highlighted compounds 5h,5f & 5i as potential templates for developing more effective antidiabetic agents. Further evaluation of the antidiabetic activity of these compounds was conducted in vivo using a type II diabetes model induced by Streptozotocin (STZ) and Nicotinamide (NA) in rats. The in vivo tests demonstrated that treatment with 5h (30 mg/kg body weight) significantly reduced fasting blood glucose levels, while 5f (30 mg/kg body weight) showed moderate reduction compared to the diabetic control group. Moreover, treatment with 5h and 5f dose- dependently decreased oxidative stress markers such as lipid peroxidation (MDA) and increased antioxidant enzyme superoxide dismutase (SOD) and glutathione (GSH) levels in the liver and pancreas. These findings establish benzimidazole Schiff bases as promising lead compounds for antidiabetic drug development, warranting further optimization and in vivo validation studies to advance their therapeutic potential.