Quinazolinone based broad-spectrum antiviral molecules: design, synthesis, in silico studies and biological...

In an attempt to develop broad-spectrum antiviral agents, we designed non-nucleoside small molecules as deubiquitinating enzyme inhibitors. The newly developed candidates are based on the quinazolinone nucleus and have been biologically evaluated as antiviral agents against four viruses: adenovirus, HSV-1, coxsackievirus, and SARS-CoV-2. Additionally, activity against papain-like protease (PL^pro), a DUB enzyme of SARS-CoV-2, was evaluated. Structure-activity association was established dependent on the obtained data. Regarding adenovirus, HSV-1, and coxsackievirus, most of the new candidates showed promising antiviral activity. Among them, compounds 8d and 8c have the highest potential, with IC₅₀ values reaching from 12.77 to 15.96 μg/mL and 16.71 to 19.58 μg/mL, respectively, compared to acyclovir's IC₅₀ of 3.45-15.97 μg/mL. However, 8c outperformed acyclovir in terms of selectivity index, with selectivity indices ranging from 19.04 to 22.31, whereas acyclovir's selectivity indices ranged from 4.77 to 22.10. While 8d had selectivity indices comparable to those of acyclovir. Interestingly, compound 8d revealed very potent activity against SARS-CoV-2, showing an IC₅₀ value of 0.948 μg/mL in comparison to IC₅₀ of 1.141 μg/mL for remdesivir. Additionally, 8d displayed a far better selectivity index than remdesivir. Furthermore, 8d showed promising inhibition of papain-like protease with an IC₅₀ of 5.056 μg/mL. In addition, the proposed binding modes and affinities of the new derivatives to papain-like protease were significant. Overall, the majority of such synthesized compounds, especially compound 8d, have shown strong antiviral activity and good safety profiles, making them promising candidates for future development in antiviral therapies.