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Background: Viral resistance to existing inhibitors and the time-dependent effectiveness of neuraminidase inhibitors have limited the number of antivirals that can be used for prophylaxis and therapeutic treatment of severe influenza infection. Thus, there is an urgent need to develop new drugs to prevent and treat influenza infection. Objective: The aim of this study was to design and synthesize a novel series of 2-ureidonicotinamide derivatives, and evaluate their anti-IAV activities. Furthermore, we predicted the abilities of these compounds inhibiting PA-PB1 subunit and forecasted the docking poses of these compounds with RNA polymerase protein (PDB ID 3CM8). Method: The novel designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their abilities inhibiting RNP and against influenza A virus. In addition, the 23 synthesized molecules were subjected to the generated pharmacophore Hypo1 to forecast the activity target PA-PB1 subunit of RNA polymerase. The ADMET pharmacokinetic parameters were calculated by the ADMET modules in Discovery Studio 2016. The docking results helped us to demonstrate the possible interactions between these compounds with 3CM8. Results: The synthesized 2-ureidonicotinamide derivatives were characterized as potent anti-influenza inhibitors. The target compounds 7b and 7c demonstrated significant antiviral activities, and could be considered as novel lead compounds of antiviral inhibitors. In addition, compound 7b revealed suitable ADME properties expressed, and might be a significant RNA polymerase inhibitor targeting PA-PB1 subunit based on the predictable results and the docking results. Conclusion: This study revealed a novel series of compounds that might be useful in the search for an effective drug against influenza virus.

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