Background: Increasing resistance has resulted in anurgent need for new antimicrobial drugs. A systematicme-too approach was chosen to modify clinically used sulfonamides to obtain their imines. Methods &results: Twenty-five compounds were synthesized and evaluated for theirantibacterial activity. The most active compounds were also investigated against methicillin- and trimethoprim/sulfamethoxazole (SMX)-resistant Gram-positive species. Staphylococci shared the highest susceptibility including resistant strains with minimum inhibitory concentrations from 3.91μM (≥2.39μg ml-1). Crucially, the compounds inhibit MRSA and trimethoprim/SMX-resistant Staphylococci without any cross-resistance. Modification of parent sulfonamides turned abacteriostatic effect into abactericidal effect. Toxicity for HepG2 and hemolyticproperties were also determined. Conclusions: The presence of adihalogenated salicylidene moiety is required for optimal activity. Based on toxicity, promising derivatives for further investigationwere identified.