EVALUATION OF ANTIDIABETIC POTENTIAL OF IMIDAZOLE LINKED ANILINE-BASED DERIVATIVES

Abstract

Diabetes mellitus is a metabolic disease characterized by abnormally high blood glucose levels. According to the World Health Organization (WHO), the prevalence is expected to rise to several millions in the coming years. There is an urgent need to develop a therapeutic strategy to combat the rising prevalence of diabetes. The current study aimed to assess the antidiabetic potential of an imidazole based novel synthetic compound, targeting antioxidant signaling pathway. Using Swiss ADME (Absorption Distribution Metabolism Excretion) and pkCSM (Predicting Small Molecule Pharmacokinetic and Toxicity) pharmacological and pharmacokinetic properties of the novel compound were predicted which showed promising results. Molecular docking of a potential antidiabetic target, DPP-IV (Dipeptidyl Peptidase-IV) with Compound (Tyrosine-TYR: A:211, Glutamine-GLN: A:123, Arginine-ARG: A:253), exhibited binding affinities that were comparable to standard drug Sitagliptin (Histidine-HIS A:740, Arginine-ARG A:358, Glutamic Acid-GLU A:205). In vitro, alpha-amylase assay showed antidiabetic potential of novel compound. For in vivo study, Synthetic Compound 10 mg/kg and NAC ((N-Acetyl Cysteine) 50 mg/kg were administered subcutaneously to STZ (Streptozotocin) induced diabetic rat model. After administering the dose, blood glucose levels were significantly reduced. In addition to this, biochemical profiling of STZ induced model, revealed a considerable rise in reactive oxygen species (ROS), TBARs (Thiobarbituric acid), liver and lipid markers together with a decrease in antioxidant enzymes SOD (Superoxide Dismutase), CAT (Catalase), APX (Ascorbate Peroxidase), POD (Peroxidase), and GSH (Reduced Glutathione) levels. Results showed antioxidant property of novel compound suggesting it has antidiabetic potential. However, treatment with NAC and compound reversed the results. Moreover, therapeutic potential of the synthesized compound was also demonstrated by baseline characteristics, such as body weight, and blood glucose of experimental groups. qRT-PCR (Quantitative Reverse Transcription Polymerase Chain Reaction) and western blot results indicated upregulated expression of FoxO3a (Forkhead box class O-3a) and NRF-1(nuclear transcription factor-1) in treatment. In conclusion, current investigation identified imidazole linked aniline-based compound as a possible therapeutic agent and a useful target for drug development