Forty-eight chalcone analogs were synthesized and their in vitro antibacterial activity against Staphylococcus aureus NCIM 5021, Bacillus subtilis NCIM 2718, Phaseolus vulgaris NCIM 2813, Escherichia coli NCIM 2931, Salmonella typhi 2501 and Enterobacter aerogenes NCIM 5139 were evaluated by microdilution broth assay. Quantitative structure-activity relationships were developed for all the cases (r2 = 0.68-0.79; = 0.58-0.78; q 2 = 0.51-0.68; F = 13.02-61.51). Size, polarizability, electron-donating/withdrawing and hydrophilic nature of the molecule determine the activity against these Gram-positive and Gram-negative bacteria. Staphylococcus aureus was the most and S. typhi was the least hydrophobic of these organisms. These chalcones act better against more hydrophobic organisms. The more active chalcones have log P between 1.5 and 3. Compound 24, one of the most active compounds, was found to act by damaging the cell wall of S. aureus. Slimicidal activity of five of the most active compounds (24, 31, 32, 34 and 37) was found to be in the range of 48-60% against S. aureus and 40-54% against E. coli. A correlation was observed among the hydrophobicity of the compounds, hydrophobicity of the bacterial cell surface and the antibacterial activity of the compound. © 2009 Blackwell Munksgaard.