Synthesis and biological evaluation of 6-hydroxychromone based thiosemicarbazones as potential antidiabetic and antioxidant agents

Abstract

A new series of 6-hydroxychromone-based thiosemicarbazones 4(a-p) was synthesized and assessed for their antidiabetic (alpha-Glucosidase and alpha-Amylase inhibition) as well as antioxidant (2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)) activities. Among the synthesized compounds, compound 4k (IC50 = 1.18 +/- 0.19 & micro;g/mL) emerged as the promising alpha-Glucosidase inhibitor, significantly outperforming the reference drug Acarbose (IC50 = 7.33 +/- 0.13 & micro;g/mL). For alpha-Amylase inhibition, compound 4 g (IC50 = 13.61 +/- 2.04 & micro;g/mL) demonstrated excellent activity, compared to Acarbose (IC50 = 43.15 +/- 5.22 & micro;g/mL). In antioxidant assays, compound 4o (IC50 = 15.30 +/- 1.70 & micro;g/mL) exhibited the strongest DPPH radical scavenging effect, and compound 4 g (IC50 = 6.06 +/- 0.15 & micro;g/mL) showed the highest ABTS scavenging activity, surpassing the standard antioxidant Trolox (IC50 = 30.20 +/- 5.14 & 18.19 +/- 2.47 & micro;g/mL, respectively). Remarkably, these derivatives showed greater efficacy compared to standard inhibitors, underscoring their promise as novel candidates for antidiabetic and antioxidant drug development. Molecular docking analysis demonstrated strong binding and critical interactions within the enzyme active sites. MD simulations confirmed the stability of 4k-alpha-Glucosidase and 4 g-alpha-Amylase, with RMSD values below 3.6 & Aring;, low RMSF (< 2.8 & Aring;) at the binding site, and sustained key interactions with Phe 158 and Tyr 151, respectively. The network pharmacology further supported the findings of molecular docking and simulation analysis.