Synthesis of Limonin Derivatives with Improved Anti-inflammatory and Analgesic Properties

Abstract

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 chemistry field. 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.