Design and biochemical evaluation of 2-cyclopropyl-thioureidobenzamide (CP-TBA) derivatives as potent HBV capsid assembly modulators targeting a novel binding site

Eur J Med Chem. 2025 May 5:289:117441. doi: 10.1016/j.ejmech.2025.117441.

Mei Wang ¹, Yutong Dou ², Aixin Li ³, Zechun Yang ⁴, Minghui Liang ⁴, Yuanyuan Liu ⁴, Yong Xie ⁵, Liyan Wang ⁶, Yuqing Cai ⁷, Yunfu Chen ⁵, Peng Xue ⁸, Xin Wang ⁹, Zhuanchang Wu ¹⁰, Peng Zhan ¹¹, Haiyong Jia ¹²

Affiliations

1 School of Pharmacy, Shandong Second Medical University, Weifang, 261053, Shandong, China; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, Shandong, China.
2 Key Laboratory of Infection and Immunity of Shandong Province and Dept. Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, 250012, Shandong, China.
3 School of Laboratory Medicine, Shandong Second Medical University, Weifang, 261053, China.
4 School of Pharmacy, Shandong Second Medical University, Weifang, 261053, Shandong, China.
5 State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan, 523871, Guangdong. China.
6 Research Center for Medical and Structural Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong Universityy, Jinan, 250012, Shandong, China.
7 School of Public Health, Shandong Second Medical University, Weifang, 261053, Shandong, China.
8 School of Public Health, Shandong Second Medical University, Weifang, 261053, Shandong, China. Electronic address: jplxp26@126.com.
9 Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Tai'an, 271018, Shandong, China. Electronic address: coala07@163.com.
10 Key Laboratory of Infection and Immunity of Shandong Province and Dept. Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, 250012, Shandong, China. Electronic address: zhuanchangwu@sdu.edu.cn.
11 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, Shandong, China. Electronic address: zhanpeng1982@sdu.edu.cn.
12 School of Pharmacy, Shandong Second Medical University, Weifang, 261053, Shandong, China. Electronic address: 502378774@163.com.

PMID: 40043535 DOI: 10.1016/j.ejmech.2025.117441

Abstract

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach in the treatment of chronic HBV Infection. In the quest for effective therapeutics against chronic Hepatitis B virus (HBV) Infection, we employed a novel binding site occupancy strategy to develop novel 2-cyclopropyl-thioureidobenzamide (CP-TBA) derivatives as potent HBV CAMs. Our diversity modification approach led to the identification of compound 17e, which demonstrated remarkable anti-HBV activity with an EC₅₀ of 0.033 μM in HepAD38 cells. Molecular insights obtained through docking and dynamics simulations have provided a comprehensive understanding of the hydrogen bonding interactions between 17e and crucial residues of the HBV core protein, while also revealing the occupation of a novel binding site by the cyclopropyl group, thereby elucidating its inhibitory mechanism. Although 17e exhibited robust metabolic stability in plasma, it underwent rapid metabolism in human liver microsomes. This study underscores the potential of CP-TBA derivatives in crafting the next generation of HBV CAMs with enhanced activity and druggability.

Keywords

Capsid assembly modulators; HBV; Solvent-exposed region; Structure-based drug design; Thioureidobenzamides.

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Description

Target

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HY-173120

HBV-IN-51

HBV Inhibitor

HBV

Infection

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