A new series of 4-phenylcoumarin derivatives was synthesized starting from (2-oxo-4-phenyl-2H-chromen-7-yloxy) acetic acid hydrazide 3. Evaluation of the target compounds for their antiviral activity against hepatitis A virus revealed that the ethylthiosemicarbazide derivative 7b was the most potent virucidal agent (IC(50)鈥?鈥?.1鈥痬ug/ml, TI鈥?鈥?3). The Schiff\'s bases 14c and 14b demonstrated the highest virustatic effects against viral adsorption and replication, respectively (14c; IC(50)鈥?鈥?.5鈥痬ug/ml, TI鈥?鈥?8 and 14b; IC(50)鈥?鈥?0.7鈥痬ug/ml, TI鈥?鈥?1). Furthermore, compounds 7b, 14b and 14c were tested against HAV 3C protease and showed significant inhibition effects (Ki鈥?鈥?.903, 0.104 and 0.217鈥痬uM, respectively). The remarkable inhibitory effect expressed by the three target compounds against HAV 3C protease prompted us to expand our research on HRV 3C protease, a structurally related enzyme of the same family, and interestingly, the three target compounds displayed significant inhibitory effect against HRV 3C protease (IC(50)鈥?鈥?6.10, 4.13 and 6.30鈥痬uM, respectively). Moreover, the active compounds 7b, 14b and 14c were docked within the pocket site of HAV 3C protease (PDB code: 2HAL) illustrating a strong H-profile with the key amino acids Gly170 and Cys172 similar to the co-crystallized ligand. Furthermore, 3D-pharmacophore and quantitative structure activity relationship (QSAR) models were generated to explore the structural requirements for the observed antiviral activity.