Rational Design, Synthesis, and Computational Assessment of Novel Benzoyl Hydrazone Derivatives as Multifunctional Antidiabetic agents Targeting α-Glucosidase, PPAR-γ and Aldose Reductase

Type 2 diabetes mellitus (T2DM) is the most common form of diabetes and has become a serious public health problem worldwide. There are various antidiabetic drugs on the market, but most of these drugs cause many side effects such as diarrhea, kidney failure, musculoskeletal pain, and enlarged urinary system infections in the clinical treatment of T2DM. Therefore, there is a need for new antidiabetic drugs that can be used orally, are safe with improved efficacy, and reduced side effects. Currently, drugs targeting aldose reductase, peroxisome proliferator-activated receptor gamma (PPAR-γ), and alpha-glucosidase (α-glucosidase) play a crucial role in the treatment of T2DM. This study focuses on the synthesis and design of a novel benzoyl hydrazone derivative as a possible inhibitor of elevated aldose reductase, based on rational drug design. Because of their potential for therapeutic use, hydrazone-type Schiff bases have been extensively studied. Among other things, these substances are known to possess antioxidant, antifungal, antibacterial, and anticancer qualities. In this study, derivatives of cinnamaldehyde and 4-Hydroxy benzhydrazide reacted in a methanolic medium to create a hydrazone-based Schiff base. The synthesized compounds were characterized using several spectroscopic methods, including ¹H NMR, FTIR, and high-resolution mass spectrometry. Additionally, they were evaluated in silico on α-glucosidase, PPAR-γ, and aldose reductase. Using molecular docking investigations with auto dock, the mechanisms of the enzyme-ligand interactions between the produced hydrazone molecules and target enzymes were investigated here. Furthermore, these drugs' pharmacokinetic appropriateness and ADME characteristics were assessed using Lipinski and Veber's guidelines. The molecule demonstrated strong ADME qualities and the highest binding affinity against PPAR-γ, aldose reductase, and aα-glucosidase. Additionally, it has been noted that the active hydrazone molecule forms hydrogen bonds with important amino acid residues on target enzymes. By significantly advancing experimental research, these data can direct the creation of novel antidiabetic medications.