Background: Since the emergence of HSV resistant strains, new antiviral agents have emerged and still are urgently needed, especially those with alternative targets.

Objective: In this work, we evaluated new quinolone derivatives as anti-HSV.

Methods: For this study, cells were infected and treated with different components to evaluate the profile of HSV replication in vitro. In addition, studies were performed to determine the pharmacokinetic toxicity and profile of the compound.

Results: Indeed the EC50 values of these promising molecules ranged between 8 μM and 32 μM. We have also showed that all compounds inhibited the expression of ICP27 viral proteins, which gives new insights in the search for new target for antiherpetic therapy. Chlorine in positions C6 and phosphonate in position C1 have shown to be important for viral inhibition. The chloroquinolone carboxamide derivatives fulfilled “Lipinsky Rule of Five” for good oral bioavailability and showed higher intestinal absorption and blood brain barrier penetration, as well as lower toxicity profile.

Conclusion: Although the inhibition activities of chloroquinolone carboxamide derivatives were lower than acyclovir, they showed different modes of action in comparison to the drugs currently available. These findings encourage us to continue pre-clinical studies for the development of new anti-HSV-1 agents.

Keywords: HSV-1, Antiviral drugs, Acyclovir, Chloroquinolone carboxamide, Viral protein, Oral bioavailability.

Graphical Abstract
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