Kai-Xia Zhang, Peng-Ru Wang, Fei Chen, Xi-Jing Qian, Lin Jia, Xiao-Juan Liu, Lin Li and Yong-Sheng Jin* Pages 1 - 7 ( 7 )
Background: Licorice is widely used as a hepatoprotective herb for thousands of years in Traditional Chinese Medicine, and its main chemical constituent glycyrrhizin (GL) is used as a treatment for chronic hepatitis in Japan for over 20 years. 18β-Glycyrrhetinic acid (GA) is the main active metabolite of GL.
Objective: Series of GA derivatives were designed and synthesized, and their anti-HCV activities were screened to investigate structure-activity relationship (SAR). Besides, their in-silico ADMET properties were analyzed to search for promising lead compound for further identification of anti-HCV terpenoid candidate.
Methods: GA derivatives were synthesized via reactions of oxidation, oxime, rearrangement, esterification and acylation, etc. In vitro anti-HCV activity of derivatives was tested on the HCV cell culture (HCVcc) system. In-silico ADMET properties analysis were performed via “pkCSM” and “SwissADME” platforms.
Results: Eighteen GA derivatives were synthesized and their structures were confirmed by MS and NMR spectrums. All compounds exhibited superior HCV inhibitory activity to that of GA. Compound 2 possessed the most potent anti-HCV activity with IC50 value of 0.79 μM, which is nearly 58 times potent than SA (a previously reported potent anti-HCV terpenoids) and >200 times than GA. SAR revealed the introduction of 3-oxo, short-chain (C1-C3) aliphatic alcohols or cyclic aliphatic amines is conducive to improving anti-HCV activity. In-silico ADMET prediction demonstrated most of the potent compounds possessed favorable ADMET properties.
Conclusion: Structural modification of GA at 3-position and 30-position is an effective approach to searching for potent anti-HCV agents. Compound 2, with the most potent anti-HCV activity and favorable in-silico ADMET properties, is a promising lead compound for further identification of anti-HCV terpenoid candidate.
glycyrrhetinic acid, derivatives, anti-HCV activity, terpenoids, ADMET.
School of Pharmacy, Second Military Medical University, Shanghai, Affiliated Changzheng hospital, Second Military Medical University, Shanghai, School of Pharmacy, Second Military Medical University, Shanghai, Faculty of Naval Medicine, Second Military Medical University, Shanghai, Department of Pharmacy, the Air Force Hospital from Eastern Theater of PLA, Nanjing, Jiangsu Province, 210002, Xiamen Medicine Research Institute, Xiamen 361003, ffiliated Changzheng hospital, Second Military Medical University, Shanghai, School of Pharmacy, Second Military Medical University, Shanghai