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.

中文翻译：

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18β-甘草次酸衍生物的合成和抗 HCV 活性及其计算机 ADMET 分析。

背景技术甘草作为保肝药材被广泛使用已有数千年历史，其主要化学成分甘草甜素(GL)在日本被用于治疗慢性肝炎已超过20年。18β-甘草次酸（GA）是GL的主要活性代谢物。目的设计合成GA系列衍生物，筛选其抗HCV活性，研究构效关系（SAR）。此外，还分析了它们的计算机 ADMET 特性，以寻找有希望的先导化合物，以进一步鉴定抗 HCV 萜类化合物候选物。方法通过氧化、肟、重排、酯化和酰化反应合成GA衍生物。在 HCV 细胞培养 (HCVcc) 系统上测试了衍生物的体外抗 HCV 活性。通过“pkCSM”和“SwissADME”平台进行计算机内 ADMET 特性分析。结果合成了18个GA衍生物，并通过MS和NMR谱证实了它们的结构。所有化合物都表现出优于 GA 的 HCV 抑制活性。化合物 2 具有最有效的抗 HCV 活性，IC50 值为 0.79 μM，是 SA（先前报道的一种有效的抗 HCV 萜类化合物）的近 58 倍，是 GA 的 200 倍以上。SAR揭示3-氧代、短链(C1-C3)脂肪醇或环状脂肪胺的引入有利于提高抗HCV活性。计算机 ADMET 预测表明，大多数有效化合物都具有良好的 ADMET 特性。结论 GA 在 3 位和 30 位的结构修饰是寻找有效的抗 HCV 药物的有效途径。化合物 2 具有最有效的抗 HCV 活性和良好的计算机 ADMET 特性，是一种有前途的先导化合物，可用于进一步鉴定抗 HCV 萜类化合物候选物。