Tetrahydroquinazoline N‐oxide derivatives inhibit reproduction of tick‐borne and mosquito‐borne flaviviruses

Abstract

Tick‐borne encephalitis virus (TBEV), yellow fever virus (YFV), and West Nile virus (WNV) are flaviviruses causing emerging arthropod‐borne infections of a great public health concern. Clinically approved drugs are not available to complement or replace the existing vaccines, which do not provide sufficient coverage. Thus, the discovery and characterization of new antiflaviviral chemotypes would advance studies in this field. In this study, a series of tetrahydroquinazoline N‐oxides was synthesized, and the antiviral activity of the compounds was assessed against TBEV, YFV, and WNV using the plaque reduction assay along with the cytotoxicity to the corresponding cell lines (porcine embryo kidney and Vero). Most of the studied compounds were active against TBEV (EC50 2 to 33 μM) and WNV (EC50 0.15 to 34 μM) and a few also demonstrated inhibitory activity against YFV (EC50 0.18 to 41 μM). To investigate the potential mechanism of action of the synthesized compounds, time‐of‐addition (TOA) experiments and virus yield reduction assays were performed for TBEV. The TOA studies suggested that the antiviral activity of the compounds should affect the early stages of the viral replication cycle after cell entry. Compounds with tetrahydroquinazoline N‐oxide scaffold show a broad spectrum of activity against flaviviruses and represent a promising chemotype for antiviral drug discovery.

3-[N,N-Bis(sulfonyl)amino]isoxazolines with Spiro-Annulated or 1,2-Annulated Cyclooctane Rings Inhibit Reproduction of Tick-Borne Encephalitis, Yellow Fever, and West Nile Viruses

“…Antiviral activity and cytotoxicity of the tested compounds were studied using plaque reduction assay and resazurin cell viability assay, respectively, as described previously [ 33 ]. Each compound was tested in at least two independent experiments.…”

“… Examples of compounds with antiviral activity against TBEV, YFV, WNV, and DENV [ 31 , 32 , 33 , 35 , 39 ]. …”

“…Thus, the development of specific anti-flaviviral drugs is still very important. Previously we have found several structural types of compounds showing antiviral activity against tick-borne encephalitis (TBEV), yellow fever (YFV), and West Nile (WNV) viruses [ 28 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. As can be seen in examples ( Figure 3 ), they possess quite a diverse structure.…”