Design, diversity-oriented synthesis and biological evaluation of novel heterocycle derivatives as non-nucleoside HBV capsid protein inhibitors

  • Eur J Med Chem. 2020 Sep 15;202:112495. doi: 10.1016/j.ejmech.2020.112495.
Haiyong Jia  1 ,  Ji Yu  2 ,  Xianhong Du  3 ,  Srinivasulu Cherukupalli  2 ,  Peng Zhan  4 ,  Xinyong Liu  5
Affiliations
  • 1. 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, PR China; School of Pharmacy, Weifang Medical University, 261053, Weifang, Shandong, PR China.
  • 2. 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, PR China.
  • 3. School of Pharmacy, Weifang Medical University, 261053, Weifang, Shandong, PR China; Department of Immunology, Key Laboratory for Experimental, Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection and Immunology, Shandong University School of Medicine, Jinan, 250012, Shandong Province, China.
  • 4. 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, PR China. Electronic address: [email protected].
  • 5. 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, PR China. Electronic address: [email protected].
PMID: 32712535 DOI: 10.1016/j.ejmech.2020.112495
Abstract

The capsid assembly is a significant phase for the hepatitis B virus (HBV) lifespan and is an essential target for anti-HBV drug discovery and development. Herein, we used scaffold hopping, bioisosterism, and pharmacophore hybrid-based strategies to design and synthesize six series of various heterocycle derivatives (pyrazole, thiazole, pyrazine, pyrimidine, and pyridine) and screened for in vitro anti-HBV non-nucleoside activity. Drug candidate NZ-4 and AT-130 were used as lead compounds. Several compounds exhibited prominent anti-HBV activity compared to lead compound NZ-4 and positive drug Lamivudine, especially compound II-8b, showed the most prominent anti-HBV DNA replication activity (IC50 = 2.2 ± 1.1 μM). Also compounds IV-8e and VII-5b showed the best in vitro anti-HBsAg secretion (IC50 = 3.8 ± 0.7 μM, CC50 > 100 μM) and anti-HBeAg secretion (IC50 = 9.7 ± 2.8 μM, CC50 > 100 μM) respectively. Besides, II-8b can interact HBV capsid protein with good affinity constants (KD = 60.0 μM), which is equivalent to lead compound NZ-4 ((KD = 50.6 μM). The preliminary structure-activity relationships (SARs) of the newly synthesized compounds were summarized, which may help researchers to discover more potent anti-HBV agents.

Keywords
Capsid protein; Diversity-oriented synthesis; HBV; Heterocycle derivatives.
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