Citation: Sheng Tang, Zong-Gen Peng, Xin Zhang, Xin-Yue Cheng, Wen-Jing Li, Jian-Dong Jiang, Ying-Hong Li, Dan-Qing Song. Synthesis and biological evaluation of 12-benzyl matrinic amide derivatives as a novel family of anti-HCV agents[J]. Chinese Chemical Letters, ;2016, 27(7): 1052-1057. doi: 10.1016/j.cclet.2016.03.006 shu

Synthesis and biological evaluation of 12-benzyl matrinic amide derivatives as a novel family of anti-HCV agents

Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China

Author Bio:

E-mail address: songdanqingsdq@hotmail.com (D.-Q. Song)
Received Date: 30 November 2015
Revised Date: 4 February 2016
Accepted Date: 4 March 2016
Available Online: 15 July 2016

Figures(4)

A new series of 12-benzyl matrinic amide/ethanamide derivatives were synthesized from matrinine (1) and evaluated for their anti-HCV activity, taking compound 2 as the lead. SAR revealed that the introduction of a suitable substituent at the N'-end ofmatrinic amide might greatly enhance the potency. Among them, matrinic acid 17 and N'-substituted matrinic amides 18a-d exhibited promising potency with low micromolar EC₅₀ values ranging from 1.03 μmol/L to 7.54 μmol/L, and better therapeutic window with SI from 66 to 132. Moreover, compound 17 displayed an excellent PK and safety profile in vivo, demonstrating good drug-like characteristics. Thus, it has been selected for further investigation, with an advantage of decreased chances of inducing drug-resistance mutations.
- Matrinic acid,
- Matrinic amide,
- Hepatitis C virus,
- Structure-activity relationship
1. [1]
  H.K. Mohd, J. Groeger, A.D. Flaxman. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence[J]. Hepatology, 2013,57:1333-1342. doi: 10.1002/hep.26141
2. [2]
  J.H. Fan, J.B. Wang, Y. Jiang. Attributable causes of liver cancer mortality and incidence in China[J]. Asian Pac. J. Cancer Prev., 2013,14:7251-7256. doi: 10.7314/APJCP.2013.14.12.7251
3. [3]
  X. Xiang, J. Lu, Z. Dong. Viral sequence evolution in Chinese genotype, 1b chronic hepatitis C patients experiencing unsuccessful interferon treatment[J]. Infect. Genet. Evol., 2011,11:382-390. doi: 10.1016/j.meegid.2010.11.011
4. [4]
  S. Susser, C. Welsch, Y. Wang. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients[J]. Hepatology, 2009,50:1709-1718. doi: 10.1002/hep.23192
5. [5]
  C. Sarrazin, T.L. Kieffer, D. Bartels. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir[J]. Gastroenterology, 2007,132:1767-1777. doi: 10.1053/j.gastro.2007.02.037
6. [6]
  A.S. Lok, D.F. Gardiner, E. Lawitz, et al., Preliminary study of two antiviral agents for hepatitis C genotype 1, N. Engl. J. Med. 366 (2012) 216-224.
7. [7]
  E. Vispo, P. Barreiro, V. Soriano. Pharmacokinetics of new oral hepatitis C antiviral drugs[J]. Expert Opin. Drug Metab. Toxicol., 2013,9:5-16. doi: 10.1517/17425255.2013.729577
8. [8]
  S.M. McConachie, S.M. Wilhelm, P.B. Kale-Pradhan. New direct-acting antivirals in hepatitis C therapy: a review of sofosbuvir, ledipasvir, daclatasvir, simeprevir, paritaprevir, ombitasvir and dasabuvir[J]. Expert Rev. Clin. Pharmacol., 2016,8:1-16.
9. [9]
  J. Guedj, H. Dahari, R.T. Pohl. Understanding silibinin's modes of action against HCV using viral kinetic modeling[J]. J. Hepatol., 2012,56:1019-1024. doi: 10.1016/j.jhep.2011.12.012
10. [10]
  A.M. Lam, C. Espiritu, S. Bansal. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus[J]. Antimicrob. Agents Chemother., 2012,56:3359-3368. doi: 10.1128/AAC.00054-12
11. [11]
  T.T. Jong, M.R. Lee, Y.C. Chiang, S.T. Chiang, Using LC/MS/MS to determine matrine, oxymatrine, ferulic acid, mangiferin, and glycyrrhizin in the Chinese medicinal preparations Shiau-feng-saan and Dang-guei-nian-tong-tang, J. Pharm. Biomed. Anal. 40 (2006) 472-477.
12. [12]
  N.N. Du, Z.G. Peng, C.W. Bi, et al., N-substituted benzyl matrinic acid derivatives inhibit hepatitis C virus (HCV) replication through down-regulating host heatstress cognate 70 (Hsc70) expression, PLOS ONE 8 (2013) e58675.
13. [13]
  N.N.Du, X. Li, Y.P.Wang, et al., Synthesis, structure-activity relationshipandbiological evaluationofnovelN-substitutedmatrinicacidderivatives ashostheat-stress cognate 70 (Hsc70) down-regulators, Bioorg. Med. Chem. Lett. 21 (2011) 4732-4735.
14. [14]
  Z.G. Peng, B. Fan, N.N. Du, et al., Small molecular compounds that inhibit hepatitis C virus replication through destabilizing heat shock cognate 70 messenger RNA, Hepatology 52 (2010) 845-853.
15. [15]
  Y.H. Li, Z.G. Peng, L.M. Gao. Synthesis and biological evaluation of sophocarpinic acid derivatives as anti-HCV agents[J]. Acta Pharm. Sin. B, 2014,4:212-307.
16. [16]
  A. Valentina, F. Vilius, K. Matthew, et al., (S)-5-Pyrrolidin-2-yl-1H-tetrazole, Org. Synth. 85 (2008) 72-87.
17. [17]
  N. Suzuki, T. Suzuki, Y. Ota, et al., Design, synthesis, and biological activity of boronic acid-based histone deacetylase inhibitors, J. Med. Chem. 52 (2009) 2909-2922.
18. [18]
  S. Tang, L. Kong, Y. Li. Novel N-benzenesulfonyl sophocarpinol derivatives as coxsackie B virus inhibitors[J]. ACS Med. Chem. Lett., 2015,6:183-186. doi: 10.1021/ml500525s
19. [19]
  C. Bi, C. Zhang, Y. Li. Synthesis and biological evaluation of sophoridinol derivatives as a novel family of potential anticancer agents[J]. ACS Med. Chem. Lett., 2014,5:1225-1229. doi: 10.1021/ml500289h
1. [1]
  Qin Cheng , Ming Huang , Qingqing Ye , Bangwei Deng , Fan Dong . Indium-based electrocatalysts for CO₂ reduction to C1 products. Chinese Chemical Letters, 2024, 35(6): 109112-. doi: 10.1016/j.cclet.2023.109112
2. [2]
  A-Yang Wang , Sheng-Hua Zhou , Mao-Yin Ran , Xin-Tao Wu , Hua Lin , Qi-Long Zhu . Regulating the key performance parameters for Hg-based IR NLO chalcogenides via bandgap engineering strategy. Chinese Chemical Letters, 2024, 35(10): 109377-. doi: 10.1016/j.cclet.2023.109377
3. [3]
  Anjing Liao , Wei Sun , Yaming Liu , Han Yan , Zhi Xia , Jian Wu . Pyrrole and pyrrolidine analogs: The promising scaffold in discovery of pesticides. Chinese Chemical Letters, 2025, 36(3): 110094-. doi: 10.1016/j.cclet.2024.110094
4. [4]
  Jia-Li Xie , Tian-Jin Xie , Yu-Jie Luo , Kai Mao , Cheng-Zhi Huang , Yuan-Fang Li , Shu-Jun Zhen . Octopus-like DNA nanostructure coupled with graphene oxide enhanced fluorescence anisotropy for hepatitis B virus DNA detection. Chinese Chemical Letters, 2024, 35(6): 109137-. doi: 10.1016/j.cclet.2023.109137
5. [5]
  Cheng-Da Zhao , Huan Yao , Shi-Yao Li , Fangfang Du , Li-Li Wang , Liu-Pan Yang . Amide naphthotubes: Biomimetic macrocycles for selective molecular recognition. Chinese Chemical Letters, 2024, 35(4): 108879-. doi: 10.1016/j.cclet.2023.108879
6. [6]
  Guoping Yang , Zhoufu Lin , Xize Zhang , Jiawei Cao , Xuejiao Chen , Yufeng Liu , Xiaoling Lin , Ke Li . Assembly of Y(Ⅲ)-containing antimonotungstates induced by malic acid with catalytic activity for the synthesis of imidazoles. Chinese Chemical Letters, 2024, 35(12): 110274-. doi: 10.1016/j.cclet.2024.110274
7. [7]
  Yulin Mao , Jingyu Ma , Jiecheng Ji , Yuliang Wang , Wanhua Wu , Cheng Yang . Crown aldoxime ethers: Their synthesis, structure, acid-catalyzed/photo-induced isomerization and adjustable guest binding. Chinese Chemical Letters, 2024, 35(11): 109927-. doi: 10.1016/j.cclet.2024.109927
8. [8]
  Zhen Liu , Zhi-Yuan Ren , Chen Yang , Xiangyi Shao , Li Chen , Xin Li . Asymmetric alkenylation reaction of benzoxazinones with diarylethylenes catalyzed by B(C₆F₅)₃/chiral phosphoric acid. Chinese Chemical Letters, 2024, 35(5): 108939-. doi: 10.1016/j.cclet.2023.108939
9. [9]
  Yiyue Ding , Qiuxiang Zhang , Lei Zhang , Qilu Yao , Gang Feng , Zhang-Hui Lu . Exceptional activity of amino-modified rGO-immobilized PdAu nanoclusters for visible light-promoted dehydrogenation of formic acid. Chinese Chemical Letters, 2024, 35(7): 109593-. doi: 10.1016/j.cclet.2024.109593
10. [10]
  Kaimin WANG , Xiong GU , Na DENG , Hongmei YU , Yanqin YE , Yulu MA . Synthesis, structure, fluorescence properties, and Hirshfeld surface analysis of three Zn(Ⅱ)/Cu(Ⅱ) complexes based on 5-(dimethylamino) isophthalic acid. Chinese Journal of Inorganic Chemistry, 2024, 40(7): 1397-1408. doi: 10.11862/CJIC.20240009
11. [11]
  Luyan Shi , Ke Zhu , Yuting Yang , Qinrui Liang , Qimin Peng , Shuqing Zhou , Tayirjan Taylor Isimjan , Xiulin Yang . Phytic acid-derivative Co₂B-CoPO_x coralloidal structure with delicate boron vacancy for enhanced hydrogen generation from sodium borohydride. Chinese Chemical Letters, 2024, 35(4): 109222-. doi: 10.1016/j.cclet.2023.109222
12. [12]
  Jing LIANG , Qian WANG , Junfeng BAI . Synthesis and structures of cdq-topological quaternary and (4, 4, 8)-c topological quinary Zn-MOFs with both oxalic acid and triazole ligands. Chinese Journal of Inorganic Chemistry, 2024, 40(11): 2186-2192. doi: 10.11862/CJIC.20240177
13. [13]
  Haitao Yin , Liang Meng , Li Li , Jiamu Xiao , Longrui Liang , Nannan Huang , Yansong Shi , Angang Zhao , Jingwen Hou . Polydopamine-modified biochar supported polylactic acid and zero-valent iron affects the functional microbial community structure for 1,1,1-trichloroethane removal in simulated groundwater. Chinese Chemical Letters, 2025, 36(1): 110313-. doi: 10.1016/j.cclet.2024.110313
14. [14]
  Ao Sun , Zipeng Li , Shuchun Li , Xiangbao Meng , Zhongtang Li , Zhongjun Li . Stereoselective synthesis of α-3-deoxy-D-manno-oct-2-ulosonic acid (α-Kdo) derivatives using a C3-p-tolylthio-substituted Kdo fluoride donor. Chinese Chemical Letters, 2025, 36(3): 109972-. doi: 10.1016/j.cclet.2024.109972
15. [15]
  Yao HUANG , Yingshu WU , Zhichun BAO , Yue HUANG , Shangfeng TANG , Ruixue LIU , Yancheng LIU , Hong LIANG . Copper complexes of anthrahydrazone bearing pyridyl side chain: Synthesis, crystal structure, anticancer activity, and DNA binding. Chinese Journal of Inorganic Chemistry, 2025, 41(1): 213-224. doi: 10.11862/CJIC.20240359
16. [16]
  Jia JI , Zhaoyang GUO , Wenni LEI , Jiawei ZHENG , Haorong QIN , Jiahong YAN , Yinling HOU , Xiaoyan XIN , Wenmin WANG . Two dinuclear Gd(Ⅲ)-based complexes constructed by a multidentate diacylhydrazone ligand: Crystal structure, magnetocaloric effect, and biological activity. Chinese Journal of Inorganic Chemistry, 2025, 41(4): 761-772. doi: 10.11862/CJIC.20240344
17. [17]
  Chunmao Yuan , Yanrong Zeng , Lei Huang , Yu Mou , Jun Jin , Ping Yi , Yanmei Li , Xiaojiang Hao . Hymoins A–C, three unusual polycyclic polyprenylated acylphloroglucinols with lipid-lowering activity from Hypericum monogynum. Chinese Chemical Letters, 2025, 36(3): 109859-. doi: 10.1016/j.cclet.2024.109859
18. [18]
  Liang Ma , Zhou Li , Zhiqiang Jiang , Xiaofeng Wu , Shixin Chang , Sónia A. C. Carabineiro , Kangle Lv . Effect of precursors on the structure and photocatalytic performance of g-C3N4 for NO oxidation and CO2 reduction. Chinese Journal of Structural Chemistry, 2024, 43(11): 100416-100416. doi: 10.1016/j.cjsc.2024.100416
19. [19]
  Tong Tong , Lezong Chen , Siying Wu , Zhong Cao , Yuanbin Song , Jun Wu . Establishment of a leucine-based poly(ester amide)s library with self-anticancer effect as nano-drug carrier for colorectal cancer treatment. Chinese Chemical Letters, 2024, 35(12): 109689-. doi: 10.1016/j.cclet.2024.109689
20. [20]
  Jian Song , Shenghui Wang , Qiuge Liu , Xiao Wang , Shuo Yuan , Hongmin Liu , Saiyang Zhang . N-Benzyl arylamide derivatives as novel and potent tubulin polymerization inhibitors against gastric cancers: Design, structure–activity relationships and biological evaluations. Chinese Chemical Letters, 2025, 36(2): 109678-. doi: 10.1016/j.cclet.2024.109678

Get Citation

PDF

XML

Metrics

PDF Downloads(1)
Abstract views(743)
HTML views(24)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142