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

被引：8

作者：

Wang, Mei ^{[1
]}

Zhang, Jian ^{[1
]}

Dou, Yutong ^{[2
,3
]}

Liang, Minghui ^{[1
]}

Xie, Yong ^{[4
]}

Xue, Peng ^{[5
]}

Liu, Linyue ^{[1
]}

Li, Chuanju ^{[6
]}

Wang, Yuanze ^{[7
]}

Tao, Feiyan ^{[5
]}

Zhang, Xiaohui ^{[8
,9
,10
]}

Hu, Huili ^{[8
,9
,10
]}

Feng, Kairui ^{[1
]}

Zhang, Lei ^{[1
]}

Wu, Zhuanchang ^{[2
,3
]}

Chen, Yunfu ^{[4
]}

Zhan, Peng ^{[11
]}

Jia, Haiyong ^{[1
]}

机构：

[1] Weifang Med Univ, Sch Pharm, Weifang 261053, Shandong, Peoples R China

[2] Shandong Univ, Key Lab Expt Teratol, Key Lab Infect & Immun Shandong Prov, Minist Educ, Jinan 250012, Shandong, Peoples R China

[3] Shandong Univ, Qilu Hosp, Cheeloo Med Coll, Sch Basic Med Sci,Dept Immunol, Jinan 250012, Shandong, Peoples R China

[4] Sunshine Lake Pharm Co Ltd, State Key Lab Antiinfect Drug Dev 2015DQ780357, Dongguan 523871, Peoples R China

[5] Weifang Med Univ, Sch Publ Hlth, Weifang 261053, Shandong, Peoples R China

[6] Jining Med Univ, Dept Rehabil, Affiliated Hosp, Jining 272000, Shandong, Peoples R China

[7] Guangzhou Lab, Guangzhou Int Bio Isl, Guangzhou 510000, Guangdong, Peoples R China

[8] Shandong Univ, Key Lab Expt Teratol, Minist Educ, Jinan 250012, Peoples R China

[9] Shandong Univ, Qilu Hosp, Cheeloo Med Coll, Sch Basic Med Sci,Dept Genet, Jinan 250012, Peoples R China

[10] Shandong Univ, Cheeloo Coll Med, Res Ctr Stem Cell & Regenerat Med, Sch Basic Med Sci,Dept Syst Biomed, Jinan 250012, Peoples R China

[11] Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Key Lab Chem Biol,Minist Educ, Jinan 250012, Shandong, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 20期

基金：

中国国家自然科学基金;

关键词：

HEPATITIS-B-VIRUS; INHIBITORS; REPLICATION; DISCOVERY;

D O I：

10.1021/acs.jmedchem.3c01022

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M) and HBV-infected HLCZ01 cells (EC50 = 0.033 mu M). 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.

引用

页码：13968 / 13990

页数：23

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