2. Academic Validation
  3. Design, synthesis, discovery and SAR of the fused tricyclic derivatives of indoline and imidazolidinone against DENV replication and infection

Design, synthesis, discovery and SAR of the fused tricyclic derivatives of indoline and imidazolidinone against DENV replication and infection

  • Bioorg Chem. 2022 Mar;120:105639. doi: 10.1016/j.bioorg.2022.105639.
Weiyi Qian 1,  Jian-Xia Xue 2,  Jinxin Xu 3,  Feng Li 1,  Guang-Feng Zhou 4,  Fang Wang 5,  Rong-Hua Luo 5,  Jinsong Liu 3,  Yong-Tang Zheng 6,  Guo-Chun Zhou 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, Jiangsu, China.
  • 2 Medical College, Kunming University of Science and Technology, Kunming 650223, Yunnan, China; 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.
  • 3 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 4 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.
  • 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 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: [email protected].
  • 7 School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, Jiangsu, China. Electronic address: [email protected].
PMID: 35093691 DOI: 10.1016/j.bioorg.2022.105639
Abstract

Dengue virus, belonging to a genus Flavivirus, caused public health problem in recent years. One controversial vaccine of DENV was approved and there is no Antiviral for the clinic treatment of DENV, therefore, efficient antivirals to DENV are of great medical significance. In this study, we conducted the design, synthesis, cell-based and target-based activity evaluation of 28 compounds based on indoline structural skeleton against DENV Infection. Among them, 13 active compounds against DENV Infection were discovered and their structure-activity relationship (SAR) was summarized. In this study, indoline carbohydrazine has derived more active compounds than indoline carboamide. It is discovered that TBS group exhibits a good pharmacophore to enhance anti-DENV activity. Further exploration indicated that post-treatment acts as effective time of addition and compound 15 targeting the post-entry stages of DENV2 viral life cycle. SPR imaging results support there are strong interaction of 13 and 15 with RdRp and compounds 13 and 15 reduce RdRp enzymatic activity, revealing that RdRp of DENV NS5 is the drug target for these series of compounds. Molecular docking deciphered the relationship of the structural feature with the putative binding mode by 13 and 15 with RdRp domain of DENV2 NS5 by hydrogen bonds and hydrophobic interactions to establish the fitted low energy conformation. Future studies will focus on designing more potent inhibitors for the treatment and prevention of dengue virus replication and Infection, and understanding the more profound underlying structural features of inhibitors and drug action of the mechanism.

Keywords

Antiviral; Dengue virus; Fused tricyclic derivatives of indoline and imidazolidinone; Post-treatment; RNA-dependent RNA polymerase (RdRp); Structure–activity relationship (SAR).

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