Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Jun 10;2(6):382-92.
doi: 10.1021/acsinfecdis.6b00041. Epub 2016 May 5.

Therapeutic Potential of Spirooxindoles as Antiviral Agents

Na Ye  1 , Haiying Chen  1 , Eric A Wold  1 , Pei-Yong Shi  1 , Jia Zhou  1
Affiliations
Review

Therapeutic Potential of Spirooxindoles as Antiviral Agents

Na Ye et al. ACS Infect Dis. .

Abstract

Antiviral therapeutics with profiles of high potency, low resistance, panserotype, and low toxicity remain challenging, and obtaining such agents continues to be an active area of therapeutic development. Due to their unique three-dimensional structural features, spirooxindoles have been identified as privileged chemotypes for antiviral drug development. Among them, spiro-pyrazolopyridone oxindoles have been recently reported as potent inhibitors of dengue virus NS4B, leading to the discovery of an orally bioavailable preclinical candidate (R)-44 with excellent in vivo efficacy in a dengue viremia mouse model. This review highlights recent advances in the development of biologically active spirooxindoles for their antiviral potential, primarily focusing on the structure-activity relationships (SARs) and modes of action, as well as future directions to achieve more potent analogues toward a viable antiviral therapy.

Keywords: DENV; HIV; RSV; antiviral agents; influenza virus; spirooxindoles.

PubMed Disclaimer

Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selected examples of natural products and pharmaceutical drugs or lead compounds with spirooxindole scaffold, which is depicted with red and blue representing two key moieties.
Figure 2
Figure 2
Selected examples of HIV protease inhibitors with spirooxindole scaffold and the cocrystal structure of 11 and HIV protease (PDB code 2IEN).
Figure 3
Figure 3
Selected examples of HIV non-nucleoside reverse transcriptase inhibitors with spirooxindole scaffold.
Figure 4
Figure 4
Structure of BMS433771 (21) and the cocrystal structure of 21 and 3-fold-symmetric cavity in prefusion RSV fusion protein (PDB code 5EA7).
Figure 5
Figure 5
Selected examples of RSV fusion inhibitors with spirooxindole scaffold.
Figure 6
Figure 6
(A) Selected examples of DENV NS4B inhibitors with spirooxindole scaffold. (B) Membrane topology and sequence alignment of the DENV NS4B protein. Reprinted with permission from ref 72. Copyright 2015 American Society for Microbiology Limited. (C) DENV-2 in vivo mouse efficacy of compound (R)-44. Reprinted with permission from ref 73.
Figure 7
Figure 7
Selected examples of other antiviral inhibitors with the spirooxindole scaffold.
See this image and copyright information in PMC

References

    1. Menendez-Arias L, Gago F. Antiviral agents: structural basis of action and rational design. Subcell Biochem. 2013;68:599–630. - PubMed
    1. De Clercq E. Highlights in antiviral drug research: antivirals at the horizon. Med Res Rev. 2013;33:1215–1248. - PMC - PubMed
    1. Antiretroviral drugs used in the treatment of HIV infection. http://www.fda.gov/ForPatients/Illness/HIVAIDS/Treatment/ucm118915.htm.
    1. De Clercq E. Antivirals and antiviral strategies. Nat Rev Microbiol. 2004;2:704–720. - PMC - PubMed
    1. Wainberg MA. Perspectives on antiviral drug development. Antiviral Res. 2009;81:1–5. - PubMed