title: Design, synthesis and evaluation of pyrazole derivatives as non-nucleoside hepatitis B virus inhibitors.
abstract: In continuation of our efforts toward the discovery of potent non-nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have employed bioisosterism and hybrid pharmacophore-based strategy to explore the chemically diverse space of bioactive compounds. In this article, the original thiazole platform was replaced with pyrazole scaffold to yield the optimal pharmacophore moieties in order to generate novel non-nucleoside HBV inhibitors with desirable potency. Some of the new compounds were able to inhibit HBV activity in the low micromolar range. In particular, compound 6a3 displayed the most potent activity against the secretion of HBsAg and HBeAg with IC50 of 24.33 μM and 2.22 μM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was investigated, which may help designing more potent molecules.
authors.affiliation: 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.
authors.forename: Haiyong
authors.initials: H
authors.lastname: Jia
authors.affiliation: 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, PR China.
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Bai
authors.affiliation: 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.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: 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, PR China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.affiliation: 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, PR China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Hepatic Diseases, Jinan Infectious Disease Hospital, Jingshi Road, 173, 250021, Jinan, Shandong, PR China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: 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: xinyongl@sdu.edu.cn.
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000187:drug effects / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000187:drug effects / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D011720:Pyrazoles
keywords: Bioisosterism; HBV; Hybrid pharmacophore-based; Non-nucleoside; SAR