Diphenyl ethers from the cultured lichen mycobiont of Graphis handelii Zahlbr

Purpose: Cultured lichen mycobionts are valuable sources of new natural compounds. Mycobiont of Graphis handelii growing in Vietnam was isolated, cultivated and chemically investigated. The crude extract of this cultured mycobiont showed potent alpha-glucosidase inhibition with an IC₅₀ value of 50 μg/mL.

Methods: Multiple chromatographic methods were applied to the extract to isolate compounds. The combination of Nuclear Magnetic Resonance analysis and high-resolution mass spectroscopy determined their chemical structures. Electrophilic bromination/chlorination was applied to obtain new derivatives using NaBr/H₂O₂ and NaCl/H₂O₂ reagents. Compounds were evaluated for enzyme inhibitory activities, including alpha-glucosidase inhibition, HIV-1 reverse transcriptase inhibition, SARS-CoV-2 main protease (M^pro) inhibition, anti-inflammatory activity, and cytotoxicity against several cancer cell lines. A molecular docking study for anti-SARS-CoV-2 was conducted to understand the inhibitory mechanism.

Results: A new diphenyl ether, handelone (1) and a known compound xylarinic acid A (2) were isolated and elucidated. Four synthetic products 6'-bromohandelone (1a), 2'-bromohandelone (1b), 2',6'-dibromohandelone (1c), and 2',6'-dichlorohandelone (1d) were prepared. Compound 1 showed good activity against M^pro with an IC₅₀ value of 5.2 μM but it showed weak or inactive activity in other tests. Other compounds were inactive in all assays.

Conclusion: A new compound, handelone (1) was isolated from the cultured mycobiont of Graphis handelii. From these compounds, four new derivatives were prepared. Compound 1 showed good activity against M^pro with an IC₅₀ value of 5.2 μM but it showed weak or inactive activity in other tests. Other compounds were inactive in all assays.