Discovery of 3-Arylquinoxaline Derivatives as Potential Anti-Dengue Virus Agents.

Chih-Hua Tseng,Cheng-Ruei Han,Kai-Wei Tang

doi:10.3390/ijms20194786

Abstract

We designed and synthesized a series of novel 3-arylquinoxaline derivatives and evaluated their biological activities as potential dengue virus (DENV) replication inhibitors. Among them, [3-(4-methoxyphenyl)quinoxalin-2-yl](phenyl)methanol (19a), [6,7-dichloro-3-(4-methoxyphenyl)quinoxalin-2-yl](phenyl)methanol (20a), and (4-methoxyphenyl)(3-phenylquinoxalin-2-yl)methanone (21b) were found to significantly inhibit the DENV RNA expression in Huh-7-DV-Fluc cells with a potency better than that of ribavirin. Compound 19a reduced DENV replication in both viral protein and messenger RNA (mRNA) levels in a dose-dependent manner and exhibited no significant cell cytotoxicity. Notably, compound 19a exhibited a half maximal effective concentration (EC50) value at 1.29 ± 0.74 μM. We further observed that the inhibitory effect of 19a on DENV replication was due to suppression of DENV-induced cyclooxygenase-2 (COX-2) expression. Docking studies also showed that 19a caused hydrophobic interactions at the active sites with Arg29, Glu31, Tyr116, Leu138, Pro139, Lys454, Arg455, and Gln529. The calculated lowest binding energy between the 19a and COX-2 was −9.10 kcal/mol. In conclusion, compound 19a might be a potential lead compound for developing an anti-DENV agent.

Highlights

Dengue virus (DENV) infections significantly increased in the past decades and, with more than half the world’s population living in areas at risk of infection, the World Health Organization estimated the true number of cases to exceed 50 million annually [1]
There are four serotypes of dengue, DENV-1, DENV-2, DENV-3, and DENV-4, and the infection severity ranges from the self-limiting dengue fever (DF) to the more serious dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), with reported ranges of 1–5% to 10–30% of cases resulting in death, respectively [2,3,4]
We synthesized certain 3-arylquinoxaline derivatives in order to evaluate their inhibitory activities of anti-DENV replication

Summary

Introduction

Dengue virus (DENV) infections significantly increased in the past decades and, with more than half the world’s population living in areas at risk of infection, the World Health Organization estimated the true number of cases to exceed 50 million annually [1]. There is no antiviral drug currently available for the treatment of dengue, potential anti-DENV drugs being tested in human clinical trials are at different stages of development. Cyclooxygenase-2 (COX-2) is one of the important mediators of inflammation in response to viral infection, and it contributes to viral replication, for example, cytomegalovirus or hepatitis C virus replication [6,7,8,9,10]. Lin et al revealed that COX-2 is an important factor for DENV replication and can serve as a potential target for developing therapeutic agents against DENV infection [11]

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