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  3. Discovery and development of labdane-oxindole hybrids as small-molecule inhibitors against chikungunya virus infection

Discovery and development of labdane-oxindole hybrids as small-molecule inhibitors against chikungunya virus infection

  • Eur J Med Chem. 2022 Feb 15;230:114110. doi: 10.1016/j.ejmech.2022.114110.
Quy Thi Ngoc Tran 1,  Regina Ching Hua Lee 2,  Hon Jin Liu 3,  Danli Ran 4,  Vincent Zhan Lin Low 5,  Dong Quang To 6,  Justin Jang Hann Chu 7,  Christina Li Lin Chai 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore. Electronic address: [email protected].
  • 2 Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, 117545, Singapore. Electronic address: [email protected].
  • 3 Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore. Electronic address: [email protected].
  • 4 Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, 81377, Munich, Germany. Electronic address: [email protected].
  • 5 Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore. Electronic address: [email protected].
  • 6 School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom. Electronic address: [email protected].
  • 7 Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, 117545, Singapore; Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, 117597, Singapore. Electronic address: [email protected].
  • 8 Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore. Electronic address: [email protected].
PMID: 35085859 DOI: 10.1016/j.ejmech.2022.114110
Abstract

Chikungunya virus (CHIKV) Infection, a febrile illness caused by a mosquito-transmitted alphavirus, has afflicted millions of people worldwide. There is currently no approved effective Antiviral treatment for CHIKV Infection. In this study, we report a new class of small-molecule CHIKV inhibitors, the oxindole-labdanes, that potently block the replication of CHIKV with good selectivity. Andrographolide, a previously reported inhibitor of CHIKV Infection, was used as the lead compound for our initial structure-activity relationship (SAR) study. From a focused library of 72 andrographolide analogues, we identified the lead compound (E)-2 with improved Antiviral activities. Further optimization of (E)-2 led to the discovery of the normal-labdane 7-chloro-oxindole (E)-42 as potent inhibitor against two low-passage CHIKV isolates from human patients with an EC50 of 1.55 μM against CHIKV-122508 and 0.14 μM against CHIKV-6708. Compound (E)-42 displayed minimal cytotoxic liability (CC50 > 100 μM), thus furnishing good selectivity relative to the host cells. Mechanistically, (E)-42 does not inactivate the viral particles but rather acts on the host cells to interfere with the viral replication, demonstrating both prophylactic and therapeutic effects. Our findings open a new avenue for the development of oxindole-labdane compounds as promising Antiviral drugs against CHIKV Infection.

Keywords

Antiviral; Arbovirus; Chikungunya; Labdane diterpenoid; Oxindole.

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