Anti-Herpetic, Anti-Dengue and Antineoplastic Activities of Simple and Heterocycle-Fused Derivatives of Terpenyl-1,4-Naphthoquinone and 1,4-Anthraquinone.

Vicky Roa-Linares,Liliana Betancur-Galvis,Verónica Tangarife-Castaño,Rodrigo Ochoa,Mª Castro,Pablo García,Yaneth Miranda-Brand,Arturo San Feliciano

doi:10.3390/molecules24071279

Abstract

Quinones are secondary metabolites of higher plants associated with many biological activities, including antiviral effects and cytotoxicity. In this study, the anti-herpetic and anti-dengue evaluation of 27 terpenyl-1,4-naphthoquinone (NQ), 1,4-anthraquinone (AQ) and heterocycle-fused quinone (HetQ) derivatives was done in vitro against Human Herpesvirus (HHV) type 1 and 2, and Dengue virus serotype 2 (DENV-2). The cytotoxicity on HeLa and Jurkat tumor cell lines was also tested. Using plaque forming unit assays, cell viability assays and molecular docking, we found that NQ 4 was the best antiviral compound, while AQ 11 was the most active and selective molecule on the tested tumor cells. NQ 4 showed a fair antiviral activity against Herpesviruses (EC50: <0.4 µg/mL, <1.28 µM) and DENV-2 (1.6 µg/mL, 5.1 µM) on pre-infective stages. Additionally, NQ 4 disrupted the viral attachment of HHV-1 to Vero cells (EC50: 0.12 µg/mL, 0.38 µM) with a very high selectivity index (SI = 1728). The in silico analysis predicted that this quinone could bind to the prefusion form of the E glycoprotein of DENV-2. These findings demonstrate that NQ 4 is a potent and highly selective antiviral compound, while suggesting its ability to prevent Herpes and Dengue infections. Additionally, AQ 11 can be considered of interest as a leader for the design of new anticancer agents.

Highlights

The compounds included in this study were selected as representative members of three families of terpenyl-1,4-NQs (1–9), 1,4-AQs (10–18) and heterocycle-fused quinone (HetQ) (19–27), and their structures are represented in Table 1 and Figure 1
Dengue virus serotype 2 (DENV-2) entry, rather ispossible mostly governed hydrophobic interactions thatasare positively induced by the preferred opposite than its attachment we found for Human Herpesvirus (HHV)-1
No interactions were formed with any of those amino acids found for NQ 4, or those reported for SA-17 [16]. Considering this information, it is possible to propose that NQ 4 acts in a similar way as SA-17, probably affecting Dengue virus (DENV)-2 entry, rather than its attachment as we found for Human Herpesvirus type 1 (HHV-1)

Summary

Introduction

Dengue disease, caused by Dengue virus (DENV), is currently the most prevalent mosquito-borne viral infection around the world, causing approximately between 50 and 200 million symptomatic cases, and 20,000 deaths per year [6]; remarkably, there are no drugs available for its treatment. Several efforts have been done to counter DENV spread via the biological and chemical mosquito control and the recent implementation of a licensed vaccine. These strategies can induce some side effects, such as selection of resistant vectors [7,8] and increased risk of illness progression to more severe grades [9]. The research of antiviral molecules to treat this disease is paramount

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Results

Conclusion