Exploring biphenylcarbonitrile–triazole–thiazolidinedione hybrids as antidiabetic agents: Synthesis, α-amylase inhibition, Molecular docking, and ADMET insights

Abstract

In this study, we synthesized a series of biphenylcarbonitrile–triazole–thiazolidinedione hybrids and evaluated their α-amylase inhibitory activity. The synthesized compounds were obtained in excellent yields and fully characterized using ¹H and ¹³C NMR, IR and mass spectrometry. Biological evaluation revealed potent α-amylase inhibition, with IC₅₀ values ranging from 1.01 to 5.14 μM. Notably, compound 5p exhibited the strongest inhibitory activity (IC₅₀ = 1.01 ± 0.02 μM), surpassing the standard drug Acarbose (IC₅₀ = 1.32 ± 0.04 μM). Furthermore, the enzyme inhibition kinetics study indicated that 5p functions as a competitive inhibitor, with K_i value of 0.47 μM. Molecular docking studies confirmed the formation of stable protein-ligand complexes within the active site of α-amylase. Additionally, ADMET predictions indicated that 5p possesses favorable pharmacokinetic properties with minimal toxicity, including the absence of hepatotoxicity and skin sensitization risks. These findings suggest that compound 5p holds promise as a potential safe and effective anti-diabetic agent.