Bioactive coumarin derivatives from Murraya exotica

Murraya exotica is a dwarf tree native to the tropical and subtropical areas of Asia with white petals. As one of the source plants of Murrayae Folium et Cacumen listed in Chinese Pharmacopoeia (2015 Edition), this herb has been extensively used for the treatment of toothache, eczema, and rheumatism. Previous chemical and pharmacological studies showed that the main active components in M. exotica are coumarins, possessing anti-inflammatory, analgesic, and antitumor activities. As an ongoing search for more new active natural products from Murraya genus, the 95% aqueous ethanol extract of the roots of M. exotica was investigated to afford 50 coumarin derivatives, including two novel heterodimers of isopentenyl-substituted indole and coumarin derivatives linked through a new fused heptacyclic ring system (1 – 2), three novel terpenophenylpropanoids formed by two isopentenyl substituted 4-hydroxycinamyl alcohol through Diels-Alder [4+2] cycloaddition and cyclic hemiacetal formation (3 – 5), and ten new coumarin derivatives (6 – 15), along with 35 known analogues (16 – 50). Their absolute configurations were determined by Mosher's method, exciton chiral method, ECD spectrum calculation, single-crystal X-ray diffraction, as well as ECD data of the in situ formed transition metal complex. The biosynthetic path way of compounds 1 – 5 were proposed based on the structural characters. Compounds 1, 4, 30, 35, and 37 showed potent inhibition against LPS-induced NO production in BV-2 microglial cells with IC50 values of 9.2 ± 0.2, 8.6 ± 0.3, 11.8 ± 0.9, 15.5 ± 0.9, and 16.9 ± 1.0 mM, respectively. Structure-activity relationship analysis indicated that the polarity and the stereo-configuration are the main factors related to the activity. Compound 31 showed remarkable inhibitory effect to ion channel protein of transient receptor potential A1 (TRPA1). In conclusion, these results revealed the possible pharmacodynamic material for the anti-inflammation and analgesic effects of M. exotica, and supplied a valuable reference for the further researches of this drug.