Abstract: With the aim of exploring the antibacterial interest of the 3-arylcoumarinic skeleton, a new series of amino/nitro substituted 3-arylcoumarins was synthesized and evaluated for their antibacterial activity against clinical isolates Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). This series was selected thinking on finding out the structural features for their antibacterial activity and selectivity. Therefore, in the present manuscript different positions of nitro, methyl, methoxy, amino and bromo substituents, under the 3-arylcoumarin scaffold, were reported. Some of these molecules exhibited antibacterial activity against S. aureus comparable to the standards – oxolinic acid and ampicillin. The best derivative of the studied series is compound 6, active and selective against S. aureus, with a MIC = 8 µg/mL. The preliminary structure-activity relationship (SAR) study showed that the antibacterial activity against S. aureus depends on the position of the substitution pattern on the 3-arylcoumarin moiety. Compound 6 will be the inspiration for the search of new active and selective antibacterial compounds.