Analogues of chlorhexidine and chemically related antimicrobial compounds were synthesized, based on a model in which the bisbiguanide moieties were replaced by conformationally restricted cyclic isosteres. This model was tested by measuring the antimicrobial activities of the compounds. Quantitative structure–activity relationship (QSAR) studies showed a parabolic dependence of antimicrobial activity on the lipophilicity of the compounds. The basicity of the functional groups in the molecules was also very important, as uncharged molecules were not able to disrupt the microbial phospholipid bilayer and cause an antimicrobial effect. We compared our QSAR results to those reported in other studies of antimicrobials of diverse structure. We found very similar QSAR models for all compounds studies with a log P (octanol/water partition constant) optimum at 5.5 (neutral log P value). The form of the QSAR equations were similar, suggesting a common mode of action for these agents.