Synthesis, structural insights and bio-evaluation of N-phenoxyethylisatin hydrazones as potent α-glucosidase inhibitors

Abstract

Effective α-glucosidase inhibitors are vital for managing type 2 diabetes, emphasizing the need for novel and potent compounds. A series of novel N-phenoxyethylisatin hydrazones 1(a–l) have been synthesized and characterized by their spectral data, and in the case of 1l by its single crystal X-ray analysis. All the synthesized compounds were in vitro evaluated for their inhibition potential against the α-glucosidase enzyme. Interestingly, most of these compounds exhibited significant inhibitory activity against the α-glucosidase enzyme, with IC₅₀ values ranging from 3.64 ± 0.13 to 94.89 ± 0.64 μM compared to the standard drug, acarbose (IC₅₀ = 873.34 ± 1.67 μM). The compound 1e was found to be the most active compound of the series having an IC₅₀ value of 3.64 ± 0.13 μM. Molecular docking studies revealed a binding score of −9.7 kcal mol⁻¹ for 1e, slightly surpassing that of acarbose (−9.4 kcal mol⁻¹). Unlike acarbose, which primarily relies on hydrogen bonding, the binding interactions of 1e are dominated by π-interactions. ADMET profiling confirmed favourable pharmacokinetics for these compounds, including good oral bioavailability, balanced hydrophilicity, and minimal predicted toxicity. These findings highlight the potential of these compounds as promising candidates for the development of more effective treatments for hyperglycemia.