2. Academic Validation
  3. Discovery of dehydroandrographolide derivatives with C19 hindered ether as potent anti-ZIKV agents with inhibitory activities to MTase of ZIKV NS5

Discovery of dehydroandrographolide derivatives with C19 hindered ether as potent anti-ZIKV agents with inhibitory activities to MTase of ZIKV NS5

  • Eur J Med Chem. 2022 Aug 27;243:114710. doi: 10.1016/j.ejmech.2022.114710.
Weiyi Qian 1,  Guang-Feng Zhou 2,  Xintong Ge 1,  Jian-Xia Xue 3,  Chang-Bo Zheng 4,  Liu-Meng Yang 5,  Xue-Rong Gu 4,  Chunyan Li 6,  Si-Dong Xiong 7,  Yong-Tang Zheng 8,  Guo-Chun Zhou 9
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, Jiangsu, China.
  • 2 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China; College of Pharmacy, Soochow University, Suzhou, 215021, China.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China; Medical College, Kunming University of Science and Technology, Kunming, 650504, Yunnan, China.
  • 4 School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, 650500, Yunnan, China.
  • 5 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China.
  • 6 College of Pharmacy, Dali University, Dali, 671000, Yunnan, China.
  • 7 College of Pharmacy, Soochow University, Suzhou, 215021, China. Electronic address: sdxiong@suda.edu.cn.
  • 8 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China. Electronic address: zhengyt@mail.kiz.ac.cn.
  • 9 School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, Jiangsu, China. Electronic address: gczhou@njtech.edu.cn.
PMID: 36055002 DOI: 10.1016/j.ejmech.2022.114710
Abstract

Infection by Zika virus (ZIKV), a mosquito-transmitted arbovirus and a member of Flavivirus, could make pediatric microcephaly and Guillain-Barré syndrome, which remains an ongoing global threat. The efficient antivirals to ZIKV Infection are of great medical need. Andrographolide and its analogues were discovered to be active against flaviviral Infection. In this study, we discovered some dehydroandrographolide derivatives of 3-oximido- or 3-alcohol-19-hindered ether to be potent anti-ZIKV agents with low cytotoxicities (CC50 > 200 μM). Time of addition assay suggests that compound 5a and its analogues act on inhibition of post-entry stage of ZIKV life cycle. It is discovered by experimental and molecular docking studies that active anti-ZIKV compounds of 3a, 5a, 5b and 5c possess inhibitory activities of ZIKV NS5 MTase (methyl transferase) enzymatic activity. Preliminary SAR reveals that C19-modification with bulky groups is necessary for anti-ZIKV Infection and replication, anti-ZIKV activity of 5a comes from itself bearing hindered trityl ether but not from its instability, the backbone of dehydroandrographolide is more effective against ZIKV Infection than that of andrographolide, and 3-oxime derivatives are more active against ZIKV Infection than 3-alcohol derivatives. To our knowledge, 5a is the first reported MTase inhibitor of andrographolide derivatives. More importantly, discovery of active compound 5b with acid-stable 19-OCHPh2 against ZIKV Infection is valued and gives us a clue to design and discover generally acid-stable anti-ZIKV agents.

Keywords

Androgrpholide and dehydroandrogrpholide; Bulky group/large volume group; Hindered ether; Methyltransferase (MTase); Oxime; Zika virus (ZIKV).

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z