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The development of new and effective antimicrobial compounds is urgent due to the emergence of resistant bacteria. Natural plant flavonoids are known to be effective molecules, but their activity and selectivity have to be increased. Based on previous aurone potency, we designed new aurone derivatives bearing acetamido and amino groups at the position 5 of the A ring and managing various monosubstitutions at the B ring. A series of 31 new aurone derivatives were first evaluated for their antimicrobial activity with five derivatives being the most active (compounds <b>10</b>, <b>12</b>, <b>15</b>, <b>16</b>, and <b>20</b>). The evaluation of their cytotoxicity on human cells and of their therapeutic index (TI) showed that compounds <b>10</b> and <b>20</b> had the highest TI. Finally, screening against a large panel of pathogens confirmed that compounds <b>10</b> and <b>20</b> possess large spectrum antimicrobial activity, including on bioweapon BSL3 strains, with MIC values as low as 0.78 µM. These results demonstrate that 5-acetamidoaurones are far more active and safer compared with 5-aminoaurones, and that benzyloxy and isopropyl substitutions at the B ring are the most promising strategy in the exploration of new antimicrobial aurones.