Solubility and stability enhancement of an andrographolide analogue through complexation with cyclodextrins: Molecular modeling and experimental validation
Issued Date
2026-04-01
Resource Type
ISSN
01677322
eISSN
18733166
Scopus ID
2-s2.0-105030412849
Journal Title
Journal of Molecular Liquids
Volume
447
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Molecular Liquids Vol.447 (2026)
Suggested Citation
Nutho B., Sawatdhiphol S., Pornsuwan S., Ali S., Aman A., Krusong K., Arsakhant P., Saeeng R., Rungrotmongkol T. Solubility and stability enhancement of an andrographolide analogue through complexation with cyclodextrins: Molecular modeling and experimental validation. Journal of Molecular Liquids Vol.447 (2026). doi:10.1016/j.molliq.2026.129374 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/115410
Title
Solubility and stability enhancement of an andrographolide analogue through complexation with cyclodextrins: Molecular modeling and experimental validation
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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 <sup>1</sup>H 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.