Surveillance of the antiviral activity and mechanism of action of newly synthesized spirocyclic thio-pyrimidinones against human adenovirus type 40

Human adenoviruses (HAdVs) cause multiple common human infections; they are responsible for several upper and lower respiratory system and gastrointestinal diseases. There are no available approved antiviral treatments specific to HAdVs thus far; only a wide-spectrum antiviral can be used, and this creates the need for potent antiviral medications to treat illnesses that pose a serious threat. On the basis of our previous research that examined spirocyclic thio-pyrimidinone derivatives against human herpes simplex virus type 2 (HSV-2), in this study, we concentrated on exploring the antiviral activity of these compounds against adenovirus type 40 (HAdV-40) and their mode of action. Spiro pyrimidinone derivative 3 showed promising antiviral activity among the eleven synthesized compounds, with a selectivity index of 11.88. Compound 3 mainly inhibited HAdV-40 during the virucidal stage by 35%, viral multiplication by 26%, and viral absorption by approximately 20%. Additionally, the downregulation of the gene expression levels of IL-6, TNF-α, CXCL10, and CCL-5 reflects the effect of compound 3 on viral suppression, indicating that the inflammatory pathway is modulated. Additionally, docking studies were performed to evaluate the 3 mechanisms of action of the compounds for viral inhibition. The results revealed some interactions that point to a potential mechanism by which compound 3 prevents the adenovirus from adhering by interfering with the ability of the short-fiber knob to function while the compound and virus are in contact.