Discovery of Exoticoumarins A-L: New Anti-Inflammatory Coumarin Derivatives from Murraya exotica

The ethanolic extract of the roots of Murraya exotica (Rutaceae) yielded twenty coumarins, including twelve previously undescribed compounds named exoticoumarins A-L (1-12; two biscoumarins, five coumarin hybrids, and five monomers). Their structures, including absolute configurations, were elucidated by a combination of NMR and HR-ESI-MS analyses, single-crystal X-ray diffraction, ECD exciton coupling, Mo₂(OAc)₄- and Rh₂(OCOCF₃)₄-induced ECD, comparison of experimental with calculated ECD spectra, and chemical hydrolysis. Anti-inflammatory evaluation in LPS-stimulated RAW264.7 macrophages identified exoticoumarins A and K (1 and 11) as potent inhibitors of nitric oxide (NO) production, with IC₅₀ values of 7.41 and 10.63 μM, respectively. Mechanistic studies revealed that 1 suppressed nitric oxide synthase (iNOS) expression at both transcriptional and translational levels, an effect associated with the inhibition of c-Jun N-terminal kinase (JNK) phosphorylation within the mitogen-activated protein kinase (MAPK) signaling pathways, without markedly affecting extracellular regulated protein kinases (ERK) 1/2 phosphorylation. These findings highlight exoticoumarin A (1) as a promising anti-inflammatory lead derived from M. exotica.