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Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Research Article

Synthesis and Anti-HCV Activities of 18β-Glycyrrhetinic Acid Derivatives and Their In-Silico ADMET Analysis

Author(s): Kai-Xia Zhang, Peng-Ru Wang, Fei Chen, Xi-Jing Qian, Lin Jia, Xiao-Juan Liu, Lin Li and Yong-Sheng Jin*

Volume 17 , Issue 6 , 2021

Published on: 27 August, 2020

Page: [831 - 837] Pages: 7

DOI: 10.2174/1573409916666200827104008

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Abstract

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 the structure-activity relationship (SAR). Besides, their in-silico ADMET properties were analyzed to search for a promising lead compound for further identification of anti-HCV terpenoid candidates.

Methods: GA derivatives were synthesized via reactions of oxidation, oxime, rearrangement, esterification and acylation. In vitro anti-HCV activity of derivatives was tested on the HCV cell culture (HCVcc) system. In-silico ADMET properties analysis was 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 an 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 that 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 candidates.

Keywords: Glycyrrhetinic acid, derivatives, anti-HCV activity, terpenoids, ADMET, GA, GL.

Graphical Abstract

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