2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Novel Thioureidobenzamide (TBA) Derivatives as HBV Capsid Assembly Modulators

Design, Synthesis, and Biological Evaluation of Novel Thioureidobenzamide (TBA) Derivatives as HBV Capsid Assembly Modulators

  • J Med Chem. 2023 Oct 15. doi: 10.1021/acs.jmedchem.3c01022.
Mei Wang 1,  Jian Zhang 1,  Yutong Dou 2,  Minghui Liang 1,  Yong Xie 3,  Peng Xue 4,  Linyue Liu 1,  Chuanju Li 5,  Yuanze Wang 6,  Feiyan Tao 4,  Xiaohui Zhang 7 8,  Huili Hu 7 8,  Kairui Feng 1,  Lei Zhang 1,  Zhuanchang Wu 2,  Yunfu Chen 3,  Peng Zhan 9,  Haiyong Jia 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, P. R. China.
  • 2 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Dept. Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College, Shandong University, Jinan 250012, Shandong, P. R. China.
  • 3 State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan 523871, P. R. China.
  • 4 School of Public Health, Weifang Medical University, Weifang 261053, Shandong, P. R. China.
  • 5 Department of Pharmacy, Affiliated Hospital of Jining Medical University, Jining 272000, Shandong, P. R. China.
  • 6 Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou 510000, Guangdong, P. R. China.
  • 7 Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College, Shandong University, Jinan 250012, P. R. China.
  • 8 The Research Center of Stem Cell and Regenerative Medicine, Department of Systems Biomedicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, P. R. China.
  • 9 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, P. R. China.
PMID: 37839070 DOI: 10.1021/acs.jmedchem.3c01022
Abstract

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV Infection. In this study, we designed and synthesized five series of benzamide derivatives based on a multisite-binding strategy at the tolerant region and diversity modification in the solvent-exposed region. Among them, thioureidobenzamide compound 17i exhibited significantly increased anti-HBV activity in HepAD38 (EC50 = 0.012 μM) and HBV-infected HLCZ01 cells (EC50 = 0.033 μM). Moreover, 17i displayed a better inhibitory effect on the assembly of HBV capsid protein compared with NVR 3-778 and a inhibitory effect similar to the clinical drug GLS4. In addition, 17i showed moderate metabolic stability in human microsomes, had excellent oral bioavailability in Sprague-Dawley (SD) rats, and inhibited HBV replication in the HBV carrier mice model, which could be considered as a promising candidate drug for further development.

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