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In terms of treatment, the widely utilized anti\u2010HSV drugs such as acyclovir have serious limitations, for example, drug resistance and side effects. Here, we have identified the guanidine\u2010modified (<jats:italic>E<\/jats:italic>,<jats:italic>E<\/jats:italic>)\u20104,6\u2010bis(styryl)\u2010pyrimidine (BS\u2010pyrimidine) derivative compound 5d as an inhibitor of HSV and further elucidated the anti\u2010HSV mechanisms of compound 5d both in vitro and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Cytopathic effect inhibition assay, plaque assay, and immunofluorescence assay were used to evaluate the anti\u2010HSV effects of compound 5d in vitro. Membrane fusion assays, immunofluorescence assays, Western blotting assays, and pull\u2010down assays were used to explore the anti\u2010HSV mechanisms of compound 5d. HSV\u20101\u2010infected mice, combined with haematoxylin\u2013eosin staining and quantitative RT\u2010PCR, were used to study the anti\u2010HSV effects of compound 5d in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The guanidine\u2010modified compound 5d rather than the un\u2010modified compound 3a effectively inhibited both HSV\u20101 and HSV\u20102 multiplication in different cell lines, more effectively than acyclovir. Compound 5d may block virus binding and post\u2010binding processes such as membrane fusion, by targeting virus gB protein. In addition, compound 5d may also down\u2010regulate the cellular PI3K\/Akt signalling pathway to interfere with HSV replication. Treatment with compound 5d also markedly improved survival and decreased viral titres in HSV\u2010infected mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Thus, the guanidine\u2010modified BS\u2010pyrimidine derivatives have the potential to be developed into novel anti\u2010HSV agents targeting both virus gB protein and cellular PI3K\/Akt signalling pathways.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14918","type":"journal-article","created":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T06:30:50Z","timestamp":1573453850000},"page":"1568-1588","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Guanidine modifications enhance the anti\u2010herpes simplex virus activity of (<i>E<\/i>,<i>E<\/i>)\u20104,6\u2010bis(styryl)\u2010pyrimidine derivatives in vitro and in 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