Dengue virus replication inhibition by dibenzothiepin derivatives

Dragos P. Mihai, George M. Nitulescu, Jessica L. Smith, Alec Hirsch, Camelia E. Stecoza

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 (IC90) 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.

Original languageEnglish (US)
JournalMedicinal Chemistry Research
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Dibenzothiepins
Thiepins
Dengue Virus
Virus Replication
Viruses
Derivatives
Scaffolds
Antiviral Agents
Dopamine D4 Receptors
HEK293 Cells
Drug Design
Antidepressive Agents
Substitution reactions
Oxidation
Research
Pharmaceutical Preparations

Keywords

  • D4 dopamine receptor antagonists
  • Dengue fever
  • Dibenzothiepin
  • Drug repurposing
  • Molecular docking
  • NS3 helicase inhibitor

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

Dengue virus replication inhibition by dibenzothiepin derivatives. / Mihai, Dragos P.; Nitulescu, George M.; Smith, Jessica L.; Hirsch, Alec; Stecoza, Camelia E.

In: Medicinal Chemistry Research, 01.01.2019.

Research output: Contribution to journalArticle

Mihai, Dragos P. ; Nitulescu, George M. ; Smith, Jessica L. ; Hirsch, Alec ; Stecoza, Camelia E. / Dengue virus replication inhibition by dibenzothiepin derivatives. In: Medicinal Chemistry Research. 2019.
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