Discovery,Synthesis And Activity Evaluation Of New Benzimidazole α-Glucosidase Inhibitors

Diabetes is one of the chronic metabolic diseases with the largest number of known complications,and more than 90%of clinical cases are type 2 diabetes.Long-term disorders of glucose metabolism increase the risk of other related fatal diseases,including stroke,kidney failure and cardiovascular disease.Pharmacological treatment is crucial to the prevention and treatment of complications.α-Glucosidase inhibitors effectively lower postprandial glucose by inhibiting the activity of variousα-glucosidases and delaying the hydrolysis of oligosaccharides into monosaccharides,making them widely used in Asia where pasta is the main food with high carbohydrate content,but the use of currently marketed drugs is mostly associated with gastrointestinal adverse effects,limiting their application.In this thesis,a compound 6a with moderateα-glucosidase inhibitory activity(IC₅₀=37.94±1.86μM)was screened from our laboratory compound library using virtual screening and found to possess a benzimidazole structural fragment.Benzimidazole is a group with a wide range of biological activities such as antitumor,antibacterial,antitubercular,and antidiabetic,etc.Literature findings show that benzimidazole derivatives have been widely used in recent years for the discovery and design of effectiveα-glucosidase inhibitor drug precursors.In this thesis,a series of derivatives based on the structure of2-phenyl-1H-benzo[d]imidazole were successfully synthesized after systematic structural modification,activity optimization,rational design of reaction routes and optimization of reaction conditions for compound 6a,and the structures of the compounds were determined by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.The inhibitory activities of all derivatives againstα-glucosidase were determined by in vitro enzymatic assays,and the most potent inhibitory activities were found for compounds 15o and22d with IC50 values of 2.09±0.04 and 0.71±0.02μM,respectively.Fluorescence quenching assays confirmed the direct binding of compounds 15o and 22d toα-glucosidase.Enzyme inhibition kinetic experiments showed that both compounds are non-competitive inhibitors ofα-glucosidase,in agreement with the results of molecular docking studies in which they bind to the variable configuration site of the enzyme.Cellular activity assessment indicated that 15o and 22d were not cytotoxic to LO2 cells.Furthermore,in vivo pharmacodynamic studies showed that compound 15o showed comparable hypoglycemic activity and improved oral sucrose tolerance to the positive control acarbose.Based on the above experimental results,we believe thatα-glucosidase inhibitor 15o can be used as a lead compound for the development of therapeutic agents for type 2 diabetes.