Design, synthesis, and in-vitro/in-vivo pharmacodynamic studies of novel aza-fused heterocyclic compounds against herpes simplex virus type 1.

Herpes simplex virus type 1 (HSV-1) is a prevalent pathogen that can lead to severe diseases, including herpes labialis, keratitis, and encephalitis. The development of novel antiviral therapies is significant due to the limited number of available treatments and the emergence of drug-resistant strains. In this study, a series of aza-fused heterocyclic derivatives were synthesized and evaluated for antiviral efficacy. Compound 5i demonstrated notable antiviral activity in vitro with an EC50 (Effective Concentration 50 %) of 1.95 ± 0.07 μM. This effect was achieved by inhibiting viral replication and targeting viral ICP4 and gD proteins. In addition, the expression of STING and NF-κB signaling pathways was down-regulated, cytokine storm was reduced, and the multi-targeted activity of compound 5i inhibited apoptosis. The high efficacy of compound 5i was demonstrated in a mouse herpes encephalitis model. Infected mice's survival significantly improved, and viral load in brain tissue was substantially reduced in the presence of compound 5i. Furthermore, compound 5i demonstrated favorable safety in preliminary in vivo evaluations, with no adverse effects on major organs observed. In conclusion, the aza-fused heterocyclic derivative 5i has substantial potential as a therapeutic agent for HSV-1 infection, providing a valuable foundation for further drug development and clinical translation.