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As part of our discovery research, the new class of aminoisothiazolamides was investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Aminoisothiazolamide 3\u2010amino\u20104\u2010chloro\u2010N\u2010(cyclohexylmethyl)isothiazole\u20105\u2010carboxamide <jats:bold>1a<\/jats:bold> and several of its derivatives displayed potent herbicidal and fungicidal <jats:italic>in vivo<\/jats:italic> activity in initial glasshouse tests. Lysyl\u2010tRNA synthetase 1 (KRS1) was identified as the putative target for <jats:bold>1a<\/jats:bold> and was validated as a key contributor to the biochemical mode\u2010of\u2010action of aminoisothiazolamides. Thermal stability shift analysis with KRS1 from <jats:italic>Arabidopsis thaliana<\/jats:italic> (<jats:italic>At<\/jats:italic>KRS1) revealed that <jats:bold>1a<\/jats:bold> specifically increased the thermostability of this enzyme, proving the KRS1 enzyme as the aminoisothiazolamide target. It turned out that the inhibition of <jats:italic>At<\/jats:italic>KRS1 and <jats:italic>Hs<\/jats:italic>KRS was strongly correlated, as was the inhibition of <jats:italic>At<\/jats:italic>KRS1 and the herbicidal activity of the aminoisothiazolamides. Hence, <jats:italic>in vivo<\/jats:italic> acute toxicity tests were initiated at a very early project stage complementing the enzyme tests.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The observed toxicological effects paired with the anticipated likelihood to overcome this problem, owing to the highly conserved active sites in different species, finally resulted in the conclusion to stop the further exploration of the otherwise promising class of herbicidal aminoisothiazolamides. Thus, we opted to discard several further herbicidal lead structures before the start of in\u2010depth investigations when sequence analyses suggested similar levels of conservation between the respective binding pockets in plants and mammalians. \u00a9 2025 The Author(s). <jats:italic>Pest Management Science<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Society of Chemical Industry.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ps.8759","type":"journal-article","created":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T01:39:26Z","timestamp":1742002766000},"page":"3956-3983","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aminoisothiazolamides, a new class of potent inhibitors of lysyl\u2010<scp>tRNA<\/scp> synthetase"],"prefix":"10.1002","volume":"81","author":[{"given":"David","family":"Bernier","sequence":"first","affiliation":[{"name":"Research &amp; Development, Disease Control, Division Crop Science Bayer SAS  Lyon France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9906-1695","authenticated-orcid":false,"given":"David M","family":"Barber","sequence":"additional","affiliation":[{"name":"Research &amp; 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