| Summary: | 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 (<b>19a</b>), [6,7-dichloro-3-(4-methoxyphenyl)quinoxalin-2-yl](phenyl)methanol (<b>20a</b>), and (4-methoxyphenyl)(3-phenylquinoxalin-2-yl)methanone (<b>21b</b>) were found to significantly inhibit the DENV RNA expression in Huh-7-DV-Fluc cells with a potency better than that of ribavirin. Compound <b>19a</b> 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 <b>19a</b> exhibited a half maximal effective concentration (EC<sub>50</sub>) value at 1.29 ± 0.74 μM. We further observed that the inhibitory effect of <b>19a</b> on DENV replication was due to suppression of DENV-induced cyclooxygenase-2 (COX-2) expression. Docking studies also showed that <b>19a</b> caused hydrophobic interactions at the active sites with Arg29, Glu31, Tyr116, Leu138, Pro139, Lys454, Arg455, and Gln529. The calculated lowest binding energy between the <b>19a</b> and COX-2 was −9.10 kcal/mol. In conclusion, compound <b>19a</b> might be a potential lead compound for developing an anti-DENV agent.
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