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Such modifications, however, unpredictably impact activity and affect target selectivity thereby hindering drug development. A survey of 5\u2019\u2019\u2010modifications of the 4,5\u2010AGAs and the related 5\u2010<jats:italic>O<\/jats:italic>\u2010furanosyl apramycin derivatives is presented. In the neomycin and the apralog series, all modifications were well\u2010tolerated, but other 4,5\u2010AGAs require a hydrogen bonding group at the 5\u2019\u2019\u2010position for maintenance of antibacterial activity. The 5\u2019\u2019\u2010amino modification resulted in parent\u2010like activity, but reduced selectivity against the human cytosolic decoding A site rendering this modification unfavorable in paromomycin, propylamycin, and ribostamycin. Installation of a 5\u2019\u2019\u2010formamido group and, to a lesser degree, a 5\u2019\u2019\u2010ureido group resulted in parent\u2010like activity without loss of selectivity. These lessons will aid the design of next\u2010generation AGAs capable of circumventing AME action while maintaining high antibacterial activity and target selectivity.<\/jats:p>","DOI":"10.1002\/cmdc.202200120","type":"journal-article","created":{"date-parts":[[2022,4,6]],"date-time":"2022-04-06T16:18:30Z","timestamp":1649261910000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Structure\u2010Activity Relationships for 5\u2032\u2032 Modifications of 4,5\u2010Aminoglycoside Antibiotics"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5877-2770","authenticated-orcid":false,"given":"Jonathan C. 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