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Antrafenine is a drug initially designed for anti-inflammation uses. In this work we have synthesized a library of its structural analogs and tested the anti-influenza activities. These analogs belong to a group of 2-(quinolin-4-yl)amino benzamides or 2-(quinolin-4-yl)amino benzoate derivatives. Best performers were identified, namely 12 , 34 , 41 , with IC 50 against A/WSN/33 (H1N1) of 5.53, 3.21 and 6.73 μM respectively. These chemicals were also effective against A/PR/8/34 (H1N1), A/HK/1/68 (H3N2) and B/Florida/04/2006 viruses. Time-of-addition study and minigenome luciferase reporter assay both supported that the compounds act on the ribonucleoprotein (RNP) components. Using 34 and 41 as representative compounds, we determined by microscale thermophoresis that this group of compounds bind to both PA C-terminal domain and the nucleoprotein (NP) which is the most abundant subunit of the RNP. Taken together, we have identified a new class of anti-influenza compounds with dual molecular targets and good potential to be further developed. The influenza viruses, especially influenza A and B subtypes, cause many deaths each year. The high mutation rate of the virus renders available therapeutics less effective with time. In this work we identify a new class of compounds, structurally similar to the anti-inflammation drug antrafenine, with good potency against influenza A strains. The IC 50 of the best performers are within low micromolar range and thus have good potential for further development. [Display omitted] • 42 novel compounds that shared structure similarities to the NSAID, antrafenine, were designed and synthesized. • The most potent compounds could inhibit different strains of influenza A and influenza B viruses. • Mechanistic studies revealed that these compounds may dually target the PA and NP proteins of the influenza virus. [ABSTRACT FROM AUTHOR]