A focused library of seven C2 and C5 modified 4- chromanones derivatives was generated by classical lineal synthesis, and tested for antimicrobial activity. The C2 and the C5 positions were derivatized with alkyl and spiro ketones, and a primary amine and benzenesulfonamides, respectively. For the C2 position, the dimethyl, and cyclohexyl derivatives were found to be mildly active (up to MIC = 256 mug/mL). In regards to the C5 position, the amine derivatives were found to have mild activity (up to MIC = 256 mug/mL) against Staphylococcus aureus (ATCC 29213) and the Nbenzenesulfonyl derivatives showed mild activity against Escherichia coli (ATCC 25922).