Six unusual monoterpene-phenylpropanoid [2 + 3] cycloadducts from Kaempferia galanga with anti-inflammatory activity.

Six unusual monoterpene-phenylpropanoid [2 + 3] cycloadducts, named kaegalangols A-F (1-6), were isolated from the rhizomes of Kaempferia galanga. Their structures were identified through comprehensive spectroscopic analyses, including 1D and 2D NMR, HRESIMS, ECD, and quantum chemical computation. Biosynthetically, these compounds were generated from a [2 + 3] cycloaddition between ethyl p-methoxycinnamate, the major constituent in K. galanga, and different monoterpenes. All compounds demonstrated anti-inflammatory activity by inhibiting nitric oxide (NO) production in LPS-stimulated RAW264.7 macrophages. Among them, compounds 1 and 2 exhibited the most potent activity against NO production with IC50 values of 15.27 and 16.31 μM, as well as Il1b mRNA expression. This study reports for the first time the occurrence of monoterpene-phenylpropanoid hybrids in K. galanga and highlights their potential as anti-inflammatory agents.