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Of note was the increased potency of two analogues against vancomycin\u2010resistant <jats:italic>Enterococci<\/jats:italic> (VRE), one of which returned a MIC of 0.5\u2005\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup>. Five analogues were found to be equipotent or more potent than the lead <jats:bold>1<\/jats:bold>. Introduction of an indole moiety resulted in the most active robenidine analogue against methicillin\u2010resistant <jats:italic>S.\u2005aureus<\/jats:italic> (MRSA), with a MIC of 1.0\u2005\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup>. Imine C=NH isosteres (C=O\/C=S) were inactive. Monomeric analogues were 16\u201364\u2005\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup> active against MRSA and VRE. An analogue that lacks the terminal hydrazide NH moiety showed modest Gram\u2010negative activity at 64\u2005\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup>. A 4\u2010<jats:italic>tert<\/jats:italic>\u2010butyl analogue was shown to be active against both Gram\u2010positive and \u2010negative strains at 16\u201364\u2005\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup>. In general, additional modifications with aromatic moieties was poorly tolerated, except with concomitant introduction of an imine C\u2010alkyl group. The activity of these analogues against MRSA and VRE ranged from 8\u2005\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup> to inactive (MIC&gt;128\u2005\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup>) with the naphthyl and indole analogues. Gram\u2010negative activity was most promising with two compounds at 16\u2005\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup> against <jats:italic>E.\u2005coli<\/jats:italic>. Against <jats:italic>P.\u2005aeruginosa<\/jats:italic>, the highest activity observed was with MIC values of 32\u2005\u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup> with another two analogues. Combined, these findings support the further development of the (<jats:italic>E<\/jats:italic>)\u20102\u2010benzylidenehydrazine\u20101\u2010carboximidamide scaffold as a promising scaffold for the development of antibiotics against Gram\u2010positive and Gram\u2010negative strains.<\/jats:p>","DOI":"10.1002\/cmdc.201800463","type":"journal-article","created":{"date-parts":[[2018,10,14]],"date-time":"2018-10-14T23:45:06Z","timestamp":1539560706000},"page":"2573-2580","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Gram\u2010Positive and Gram\u2010Negative Antibiotic Activity of Asymmetric and Monomeric Robenidine Analogues"],"prefix":"10.1002","volume":"13","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 2308 NSW 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; Life Sciences The University of Newcastle  University Drive Callaghan 2308 NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5758-6044","authenticated-orcid":false,"given":"Hongfei","family":"Pi","sequence":"additional","affiliation":[{"name":"Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences University of Adelaide Roseworthy Campus  Mudla Wirra Road Roseworthy 5371 SA Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9806-9959","authenticated-orcid":false,"given":"Manouchehr","family":"Khazandi","sequence":"additional","affiliation":[{"name":"Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences University of Adelaide Roseworthy Campus  Mudla Wirra Road Roseworthy 5371 SA Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9308-5629","authenticated-orcid":false,"given":"Abiodun D.","family":"Ogunniyi","sequence":"additional","affiliation":[{"name":"Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences University of Adelaide Roseworthy Campus  Mudla Wirra Road Roseworthy 5371 SA Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7252-4693","authenticated-orcid":false,"given":"Kelly A.","family":"Young","sequence":"additional","affiliation":[{"name":"Chemistry, School of Environmental &amp; Life Sciences The University of Newcastle  University Drive Callaghan 2308 NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9560-301X","authenticated-orcid":false,"given":"Jennifer R.","family":"Baker","sequence":"additional","affiliation":[{"name":"Chemistry, School of Environmental &amp; Life Sciences The University of Newcastle  University Drive Callaghan 2308 NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3609-9316","authenticated-orcid":false,"given":"Siobhann N.","family":"McCluskey","sequence":"additional","affiliation":[{"name":"Chemistry, School of Environmental &amp; Life Sciences The University of Newcastle  University Drive Callaghan 2308 NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5312-2149","authenticated-orcid":false,"given":"Stephen W.","family":"Page","sequence":"additional","affiliation":[{"name":"Neoculi Pty. 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