Dengue virus replication inhibition by dibenzothiepin derivatives

The presented research uses both a target-based drug design strategy focused on dengue virus (DENV) helicase, and the repurposing of a known scaffold, the dibenzo[b,e]thiepine moiety, extensively used in antidepressants drugs. A series of dihydrodibenzo[b,e]thiepin derivatives were synthesized and t...

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Bibliographic Details
Published in:Medicinal chemistry research 2019-03, Vol.28 (3), p.320-328
Main Authors: Mihai, Dragos P., Nitulescu, George M., Smith, Jessica L., Hirsch, Alec J., Stecoza, Camelia E.
Format: Article
Language:English
Subjects:
Antidepressants
Antiviral agents
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cell Biology
Dengue fever
Derivatives
DNA helicase
Dopamine
Dopamine D4 receptors
Drug development
Molecular docking
Organic chemistry
Original Research
Oxidation
Pharmacology/Toxicology
Receptors
Replication
Scaffolds
Viral diseases
Viruses
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Summary:The presented research uses both a target-based drug design strategy focused on dengue virus (DENV) helicase, and the repurposing of a known scaffold, the dibenzo[b,e]thiepine moiety, extensively used in antidepressants drugs. A series of dihydrodibenzo[b,e]thiepin derivatives were synthesized and tested at 10 µg/mL in HEK293 cells infected with DENV2. The replication inhibitory effect was average and depends on the chemical structure. The best antiviral effect was recorded for compounds, ( E )-(2-methyl-6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)amino butanoate (TM3) and ( E )-(2-methyl-6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)amino 3-fluorobenzoate (TM24); the concentrations resulting in a 90% (1 log) inhibiton of viral titers (IC 90 ) being calculated at 10 µM for TM3 and 0.25 µM for TM24. A molecular docking study has been conducted in order to predict the binding affinity of the tested compounds to DENV2 NS3 helicase and also on dopamine D4 receptor and to establish an in silico–in vitro correlation. The results obtained indicate that the antiviral mechanisms are complex and differ significantly depending on the structure. The majority of compounds appear to inhibit only the viral helicase, some of them both helicase and D4 receptors, and in the case of one compound the mechanism is elusive. We also observed that a 2-methyl substitution and S-oxidation on the dibenzo[b,e]thiepin scaffold significantly improves the inhibition of the viral replication.
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-018-02286-1