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New urea derivatives (Series\u20101) were generally inactive, probably due to their preference for <jats:italic>cis<\/jats:italic>\u2010<jats:italic>trans<\/jats:italic> conformation (confirmed by density functional theory calculations and experimentally by nuclear overhauser effect spectroscopy NMR). Series\u20102 (3\u2010benzamidopyrazine\u20102\u2010carboxamides with disubstituted benzene ring) demonstrated that substituents larger than fluorine are not tolerated in the <jats:italic>ortho<\/jats:italic> position of the benzene ring. This series brought two new compounds (<jats:bold>21<\/jats:bold>: R\u2009=\u20092\u2010F, 4\u2010Cl and <jats:bold>22<\/jats:bold>: R\u2009=\u20092\u2010F, 4\u2010Br) with in vitro activity against <jats:italic>Mycobacterium tuberculosis<\/jats:italic> H37Rv as well as multidrug\u2010resistant clinical isolates, with minimum inhibitory concentration ranging from 6.25 to 25\u2009\u03bcg\/mL. The lactone\u2010type derivatives 4<jats:italic>H<\/jats:italic>\u2010pyrazino[2,3\u2010<jats:italic>d<\/jats:italic>][1,3]oxazin\u20104\u2010ones (Series\u20103) were inactive, but solvent stability studies of compound <jats:bold>29<\/jats:bold> indicated that they might be developed to usable lactone prodrugs of inhibitors of mycobacterial aspartate decarboxylase (PanD).<\/jats:p>","DOI":"10.1002\/ardp.202400171","type":"journal-article","created":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T01:54:56Z","timestamp":1715046896000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A hit expansion of 3\u2010benzamidopyrazine\u20102\u2010carboxamide: Toward\u00a0inhibitors of prolyl\u2010tRNA synthetase with antimycobacterial activity"],"prefix":"10.1002","volume":"357","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3327-3078","authenticated-orcid":false,"given":"Vinod Sukanth 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