Solubility and stability enhancement of an andrographolide analogue through complexation with cyclodextrins: Molecular modeling and experimental validation

Abstract

The 12-dithiocarbamate-14-deoxyandrographolide analogue (R , S)- 3l exhibits strong inhibitory activity against the SARS-CoV-2 main protease, but its poor aqueous solubility limits its pharmaceutical potential. To address this limitation, supramolecular inclusion complexes were formed between (R , S)- 3l and β-cyclodextrin (βCD), γ-cyclodextrin (γCD), and four βCD derivatives to identify the most effective carrier. An in silico strategy combining molecular dynamics simulations, binding free energy calculations, and free energy surface analysis identified sulfobutylether-β-cyclodextrin (SBEβCD) as the most stable and energetically favorable host. Experimental validation through phase solubility studies revealed a 1:1 (A<inf>L</inf>-type) inclusion complex with the highest stability constant. Further characterization using scanning electron microscopy, differential scanning calorimetry, Fourier-transform infrared, and ¹H NMR spectroscopy consistently demonstrated successful complex formation and the transformation of (R , S)- 3l into an amorphous solid phase. Overall, these findings show that complexation with SBEβCD markedly enhances the solubility and physicochemical stability of (R , S)- 3l , overcoming a key limitation in its pharmaceutical development. The integrated computational–experimental approach provides a rational framework for designing CD-based delivery systems for poorly soluble natural product derivatives and supports the advancement of andrographolide-inspired antiviral therapeutics.