New 4-phenylcoumarin derivatives as potent 3C protease inhibitors: Design, synthesis, anti-HAV effect and molecular modeling

Abstract A new series of 4-phenylcoumarin derivatives was synthesized starting from (2-oxo-4-phenyl-2 H -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  = 3.1 μg/ml, TI  = 83). The Schiff's bases 14c and 14b demonstrated the highest virustatic effects against viral adsorption and replication, respectively ( 14c ; IC 50  = 8.5 μg/ml, TI  = 88 and 14b ; IC 50  = 10.7 μg/ml, TI  = 91). Furthermore, compounds 7b , 14b and 14c were tested against HAV 3C protease and showed significant inhibition effects ( Ki =  1.903, 0.104 and 0.217 μM, 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  =  16.10, 4.13 and 6.30 μM, 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.