Background: Limonoids represent an important class of natural products which possess a
broad range of biological activities. Albeit their enormous potentials as therapeutic candidates, they
usually suffer from low bioavailability, poor aqueous solubility and relatively weak biological
activities which result in significant challenges in the clinic applications. Therefore, the exploration
and development of novel limonin derivatives with improved drug-like properties through the
structural modifications recently have attracted great attention in the biological and medicinal
Methods: Based on the structural modifications of C17-furan ring in limonin, a series of limonin
derivatives was designed, synthesized and screened for their anti-inflammatory and analgesic
activities in vivo.
Results and Conclusion: Preliminary pharmacological studies revealed that most tested compounds
exhibited more potent anti-inflammatory and analgesic efficacies than lead molecule limonin.
Especially, for compound 3f, it exhibited a stronger anti-inflammatory effect than that of naproxen
and comparable analgesic potency with aspirin. In the formalin test, 3f showed an obviously
attenuated phase-II pain response which indicated that it may produce an anti-inflammatory effect in
the periphery. Furthermore, the significantly low hERG inhibition (IC50 >100 μM) and high LD50
value of target molecule 3f further demonstrated it as a promising analgesic/anti-inflammatory
candidate with excellent drug-like profiles.