Design, synthesis, and biological evaluation of novel sulfamoylbenzamide derivatives as HBV capsid assembly modulators

• Published in: Bioorganic chemistry 2022-12, Vol.129, p.106192-106192, Article 106192
• Main Authors: Wang, Shuo, Ren, Yujie, Li, Qilan, Wang, Ya, Jiang, Xiangyi, Xu, Shujing, Zhang, Xujie, Zhao, Shujie, Bradley, Daniel P., Woodson, Molly E., Zhao, Fabao, Wu, Shuo, Li, Yuhuan, Tian, Ye, Liu, Xinyong, Tavis, John E., Zhan, Peng
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Boronic acid; Capsid - drug effects; Capsid - metabolism; Capsid assembly modulators; Capsid Proteins - metabolism; Drug Design; HBV; Hepatitis B virus - drug effects; Hepatitis B virus - physiology; Humans; Structure-based drug design; Sulfamoylbenzamide; Virus Assembly - drug effects
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.106192

[Display omitted] •All 34 compounds were evaluated for their anti-HBV activity and cytotoxicity.•Compound 7b (EC50 = 0.83 ± 0.33 µM) displayed comparable anti-HBV activity to NVR3-778 (EC50 = 0.73 ± 0.20 µM).•Compound 7b (328.8 µg/mL, pH 7) displayed better solubility than NVR 3-778 (35.8 µg/mL, pH 7) as designed.•Size exclusion chromatography and quantification of encapsidated RNA were performed to investigate the antiviral mechanism.•Molecular dynamics simulation was conducted to understand key interactions of novel derivatives with the binding pocket. Capsid assembly modulators (CAMs) represent a novel class of antiviral agents targeting hepatitis B virus (HBV) capsid to disrupt the assembly process. NVR 3-778 is the first CAM to demonstrate antiviral activity in patients infected with HBV. However, the relatively low aqueous solubility and moderate activity in the human body halted further development of NVR 3-778. To improve the anti-HBV activity and the drug-like properties of NVR 3-778, we designed and synthesized a series of NVR 3-778 derivatives. Notably, phenylboronic acid-bearing compound 7b (EC50 = 0.83 ± 0.33 µM, CC50 = 19.4 ± 5.0 µM) displayed comparable anti-HBV activity to NVR 3-778 (EC50 = 0.73 ± 0.20 µM, CC50 = 23.4 ± 7.0 µM). Besides, 7b showed improved water solubility (328.8 µg/mL, pH 7) compared to NVR 3-778 (35.8 µg/mL, pH 7). Size exclusion chromatography (SEC) and quantification of encapsidated viral RNA were used to demonstrate that 7b behaves as a class II CAM similar to NVR 3-778. Moreover, molecular dynamics (MD) simulations were conducted to rationalize the structure–activity relationships (SARs) of these novel derivatives and to understand their key interactions with the binding pocket, which provide useful indications for guiding the further rational design of more effective anti-HBV drugs.