2. Academic Validation
  3. Multisite Occupancy and Multidimensional Optimization: Design and Evaluation of Piperazine-Thioureidobenzamide Derivatives as Potent HBV Capsid Assembly Modulators

Multisite Occupancy and Multidimensional Optimization: Design and Evaluation of Piperazine-Thioureidobenzamide Derivatives as Potent HBV Capsid Assembly Modulators

  • J Med Chem. 2025 Nov 27;68(22):24358-24380. doi: 10.1021/acs.jmedchem.5c02347.
Minghui Liang 1,  Yutong Dou 2,  Jian Zhang 1,  Zechun Yang 1,  Yuanyuan Liu 1,  Mei Wang 3,  Yiyan Mao 1,  Lindan Guan 2,  Aixin Li 4,  Yuqing Cai 5,  Yan Wang 5,  Peng Xue 5,  Lei Zhang 1,  Zhuanchang Wu 2,  Xinyong Liu 3,  Peng Zhan 3,  Haiyong Jia 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Shandong Second Medical University, Weifang 261053, Shandong, PR China.
  • 2 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, Dept. Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan 250012, Shandong, PR China.
  • 3 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, PR China.
  • 4 School of Laboratory Medicine, Shandong Second Medical University, Weifang 261053, China.
  • 5 School of Public Health, Shandong Second Medical University, Weifang 261053, Shandong, China.
PMID: 41212139 DOI: 10.1021/acs.jmedchem.5c02347
Abstract

Hepatitis B virus (HBV) capsid assembly modulators are a promising class of agents for chronic HBV Infection. Thioureidobenzamide compound 17i exhibits potent anti-HBV activity but suffers from poor water solubility, high cytotoxicity, and limited drug-like properties. Herein, we report the design of piperazine-thioureidobenzamide derivatives via multisite occupancy and multidimensional optimization strategies. The representative compound 35a exhibited potent anti-HBV activity and low cytotoxicity in HepAD38 cells (EC50 = 0.020 μM, CC50 > 100 μM) and HLCZ01 cells (EC50 = 0.024 μM, CC50 > 100 μM). Molecular dynamics simulations revealed that 35a retained critical hydrogen bonds with Trp-102, Thr-128, and Leu-140, while forming new hydrogen bonds with Ser-106, Thr-142, and Asn-136. Multidimensional optimization endowed 35a with improved solubility, ideal LogP and high plasma stability. In HBV carrier mouse models, 35a inhibited viral replication more effectively than 17i, highlighting its potential as a promising candidate drug for further development.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-179393
    HBV抑制剂
    HBV
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