Compound 3a(Mansoura University)

A new series of 4-substituted oxycoumarin scaffolds was designed, synthesized, and evaluated for antiviral activity against both SARS-CoV-2 and HSV-2 viruses. Results indicated that compounds 3a, 4a, 4d, and 6d were found to be the most active members against SARS-CoV-2 with IC₅₀ values of 11.17-16.65 μg/mL, with respect to acyclovir (IC₅₀ 15.94 μg/mL). On the other hand, compounds 3a, 4a, 6b, 6c, and 6d had the best antiviral activity against HSV-2, with IC₅₀ ranging from 20.41 to 23.55 μg/mL in comparison to acyclovir (IC₅₀ 13.07 μg/mL) as a reference drug. A dual mechanistic study for active compounds against SARS-CoV-2 was performed against both 3CL protease and RNA polymerase while the DNA binding mechanism for HSV-2 was tested. Compounds 3a and 4a exhibited excellent inhibitory activity against the 3CL protease enzyme with IC₅₀s of 2.061 and 1.356 μg/mL, respectively, against tipranavir (IC₅₀ 7.057 μg/mL). In addition, compound 4a exhibited a good RNA-dependent RNA polymerase inhibitory activity, showing IC₅₀ 1.072 μg/mL against remdesivir (IC₅₀ 0.541 μg/mL). HSV-2 inhibition activity was mechanistically studied through DNA binding, where it was found that compounds 6c and 6d showed good DNA binding affinity with IC₅₀ of 36.18 and 42.7 μg/mL, respectively, against doxorubicin (IC₅₀ 31.54 μg/mL). Molecular docking studies were performed on SARS 3CL protease, RNA polymerase enzymes, and HSV-2 double-stranded DNA. Docking results exhibited excellent agreement with the obtained biological results. Physicochemical parameters and pharmacokinetic profile studies for the most active candidates, which were obtained from software calculations, proved credible drug-likeness that might act as good orally active antiviral scaffolds.