Synthesis and Inhibitory Activity of Curculigoside A Derivatives as Potential Anti-Diabetic Agents with β-Cell Apoptosis

• It is the aim to synthesize aglycone of curculigoside A derivatives using acyl chloride in a mild condition by using imidazole and operating at room temperature. • Compounds 1, 2 , and 6 inhibit α-glucosidase are more effectively than acarbose. • Compounds 3, 4 , and 6 are inhibited TNF-α receptors better than or comparable to acarbose • Compound 6 has the potential to be an anti-diabetic by improving insulin resistance as well as inducing β-cell death. Diabetes mellitus (T1D, T2D, and DD) is a chronic metabolic condition that affected 4.2 million people in 2019 and is expected to reach 700 million by 2045. Hybrid or double diabetes (DD), which presents symptoms of both T1D and T2D, is caused by β-cell failure and apoptosis. The aglycone of curculigoside A derivatives was assessed in silico to optimize the pharmacokinetics and safety profile, as well as the binding mechanism and stability of anti-diabetic medicines with α-glucosidase. The objectives of this study are to synthesize, evaluate the biological activity of α-glucosidase, and simulate the inhibitory activity of the aglycone of curculigoside A derivatives on the tumor necrosis factor alpha (TNF-α) receptor as prospective anti-diabetic agents with β-cell apoptosis. Synthesis was carried out by using the esterification technique with halogenated carboxylic acids under moderate reaction conditions. Synthesized compounds 1 - 6 were assessed for their insulin resistance using α-glucosidase and investigated in silico by using the TNF-α receptor for its action in β-cell destruction. Compounds 3 - 6 have pharmacochemical properties that can be absorbed in the gastrointestinal tract, whereas compounds 1 and 2 are more water-soluble. The proposed methodology for the synthesis of the aglycone of curculigoside A derivatives by the esterification technique using halogenated carboxylic acids under moderate reaction conditions gives good yields. The biological evaluation study indicates that compounds 1, 2 , and 6 inhibit α-glucosidase more effectively than acarbose. By in silico study, compounds 3, 4 , and 6 inhibited TNF-α receptors are better than or comparable to acarbose, indicating that they have the ability to reduce β-cell apoptosis. In conclusion, 4-hydroxybenzyl-4-fluorobenzoat (compound 6 ) has the potential to be an anti-diabetic by inducing β-cell death.