Synthesis and Antidiabetic Evaluation of Novel Andrographolide Derivatives: A Comprehensive Study on Semisynthetic Modifications and their Biological Activity

Abstract

Background and Objective: Andrographis paniculata commonly known as King of Bitters, is a traditional medicinal plant extensively used in Ayurvedic and traditional Chinese medicine systems. Andrographolide, the major bioactive diterpenoid lactone of this plant, exhibits significant therapeutic potential but faces limitations due to poor solubility and low bioavailability. This study aimed to synthesize novel semisynthetic derivatives of andrographolide and evaluate their antidiabetic activity through comprehensive biological screening and molecular docking studies.

Methods: Four semisynthetic derivatives (L-1, L-2, L-3, and L-4) were synthesized through controlled chemical modifications involving esterification, alkylation, and cyclization reactions. The compounds were characterized using spectroscopic techniques including IR, NMR, and mass spectrometry. Antidiabetic potential was evaluated through α-glucosidase and α-amylase inhibition assays, followed by in vivo studies using streptozotocin (STZ)-induced diabetic rats. Molecular docking studies were performed to predict binding affinities with target enzymes.

 Results: Among the synthesized derivatives, L-2 and L-3 demonstrated superior enzyme inhibitory activity with IC₅₀ values of 45.8 ± 8.6 and 50.2 ± 7.9 μg/mL against α-glucosidase, and 38.4 ± 5.4 and 41.5 ± 6.3 μg/mL against α-amylase, respectively, compared to acarbose (35.2 ± 4.2 and 30.5 ± 3.8 μg/mL). In vivo studies revealed significant glucose-lowering effects, with L-2 and L-3 reducing blood glucose levels by 58.5% and 56.5% respectively at 400 mg/kg dose. Molecular docking scores indicated strong binding affinities (8.1 and 8.2) for L-2 and L-3 with α-glucosidase.

Conclusion: The semisynthetic derivatives L-2 and L-3 exhibited potent antidiabetic activity superior to parent andrographolide, demonstrating their potential as novel therapeutic agents for diabetes management. The structural modifications enhanced binding affinity and biological activity, supporting further development for clinical applications.