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Although natural aminoglycosides are well\u2010characterized A\u2010site binding ligands, high off\u2010target effects and the growing emergence of bacterial resistance against aminoglycosides limit their clinical use. To circumvent these concerns with the aminoglycoside family, non\u2010aminoglycoside A\u2010site binding ligands have great potential as novel antibiotics against bacterial infections. This work describes a new class of small heterocyclic ligands based on the 2\u2010amino\u20105,6,7\u2010trimethyl\u20101,8\u2010naphthyridine (ATMND) structure for the bacterial (<jats:italic>Escherichia coli<\/jats:italic>) A\u2010site. ATMND possessing an aminoethyl side chain is found to strongly and selectively bind to the internal loop of the A\u2010site (<jats:italic>K<\/jats:italic><jats:sub>d<\/jats:sub>=0.44\u2005\u03bc<jats:sc>m<\/jats:sc>; pH\u20057.0, <jats:italic>I<\/jats:italic>=0.06\u2009<jats:sc>m<\/jats:sc>, 5\u2009\u00b0C). Significantly, this ligand shows the tightest binding reported to date among non\u2010aminoglycoside ligands. The binding study based on the thermodynamics and molecular modelling reveals key molecular interactions of ATMND\u2010C<jats:sub>2<\/jats:sub>\u2010NH<jats:sub>2<\/jats:sub> for high affinity to the A\u2010site. This ligand is also demonstrated to be applicable to the fluorescence indicator displacement assay for assessing ligand\/A\u2010site interactions.<\/jats:p>","DOI":"10.1002\/chem.201802320","type":"journal-article","created":{"date-parts":[[2018,7,3]],"date-time":"2018-07-03T22:09:42Z","timestamp":1530655782000},"page":"13862-13870","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Fluorescent Trimethylated Naphthyridine Derivative with an Aminoalkyl Side Chain as the Tightest Non\u2010aminoglycoside Ligand for the Bacterial A\u2010site RNA"],"prefix":"10.1002","volume":"24","author":[{"given":"Yusuke","family":"Sato","sequence":"first","affiliation":[{"name":"Department of Chemistry Graduate School of Science Tohoku University  Sendai 980-8578 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Rokugawa","sequence":"additional","affiliation":[{"name":"Department of Chemistry 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