Aminoglycoside mimetics inhibit bacterial translation by interfering with the ribosomal decoding site. To elucidate the structural properties of these compounds important for antibacterial activity, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to a set of 56 aminoglycosides mimetics. The successful CoMFA model yielded the leave-one-out (LOO) cross-validated correlation coefficient (q(2)) of 0.708 and a non-cross-validated correlation coefficient (r(2)) of 0.967. CoMSIA model gave q(2)=0.556 and r(2)=0.935. The CoMFA and CoMSIA models were validated with 36 test set compounds and showed a good r(pred)(2) of 0.624 and 0.640, respectively. Contour maps of the two QSAR approaches show that electronic effects dominantly determine the binding affinities. These obtained results were agreed well with the experimental observations and docking studies. The results not only lead to a better understanding of structural requirements of bacterial translation inhibitors but also can help in the design of novel bacterial translation inhibitors.