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Herein we describe the structure\u2010activity relationship development of a novel series of guanidine to 2\u2010aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2\u2010NH<jats:sub>2<\/jats:sub> pyrimidine moiety renders these analogues inactive. Introduction of a central 2\u2010NH<jats:sub>2<\/jats:sub> triazine moiety saw a 10\u2010fold activity reduction. Phenyl to cyclohexyl isosteres were inactive. The 4\u2010BrPh and 4\u2010CH<jats:sub>3<\/jats:sub>Ph with MIC values of 2 and 4\u2005\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup>, against MRSA and VRE respectively, are promising candidates for future development.<\/jats:p>","DOI":"10.1002\/open.201800241","type":"journal-article","created":{"date-parts":[[2019,7,4]],"date-time":"2019-07-04T11:37:32Z","timestamp":1562240252000},"page":"896-907","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Discovery of 4,6\u2010bis(2\u2010((<i>E<\/i>)\u2010benzylidene)hydrazinyl)pyrimidin\u20102\u2010Amine with Antibiotic Activity"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8401-5856","authenticated-orcid":false,"given":"Cecilia C.","family":"Russell","sequence":"first","affiliation":[{"name":"Chemistry, School of Environmental &amp; Life Sciences The University of Newcastle  University Drive Callaghan NSW 2308 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5114-9134","authenticated-orcid":false,"given":"Andrew","family":"Stevens","sequence":"additional","affiliation":[{"name":"Chemistry, School of Environmental &amp; 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