Relationship between structures and antibacterial activities of 22 2-(4-substituted-phenyl)-3- isothiazolinones was studied using both density functional theory (DFT) and stepwise multiple linear regression analysis (SMLR) methods. The equilibrium geometries, the frontier molecular orbital compositions and the distribution of Mulliken charges of these compounds have been investigated and analyzed using the DFT method at the B3LYP/6-311G(d,p) basis set. It was concluded that the S(1) and N(2) atoms were the active sites. Compared with the corresponding unsubstituted analogues, the 5-chloro derivatives were more active against Escherichia coli. The obtained QSAR model indicates that the nucleophilic frontier electron density of S(1) atom ( ), 3D-Balaban index (J_3D), the Wiberg bond order of S(1)—N(2) (BO_S(1)—N(2)) and Schultz molecular topological index by valence vertex degrees (SMTIV) are the predominant factors affecting antibacterial activity against Escherichia coli ATCC 8739 (Gram-negative bacteria), which could provide theoretical reference to design isothiazolinones with stronger antibacterial activity.

Key words: 3-isothiazolinone, antibacterial activity, Escherichia coli, density functional theory, QSAR