Quantitative structure-activity relationship analysis of 4-trifluoromethylimidazole derivatives with the concept of absolute hardness

A semiempirical molecular-orbital method (CAChe) was applied to delineate the relationship between the cytotoxicity (evaluated by 50% cytotoxic concentration, CC50) of thirteen 4-trifluoromethylimidazole derivatives and thirteen chemical descriptors derived by the CONFLEX/PM3 method. There was a highly significant relationship between CC50 and absolute electron negativity (chi). When the CC50 was plotted vs. the octanol-water distribution coefficient (log-P), a parabolic curve was produced, with a maximum cytotoxicity (or the least CC50 value) at log-P of 4.4. On the other hand, there was no significant relationship between CC50 and heat of formation, stability of hydration, dipole moment, ionization potential, energy of highest occupied moleculer orbital (E-HOMO), molecular weight, or absolute hardness (eta). The present study demonstrates that the biological activity of 4-trifluoromethylimidazole derivatives can be estimated by an eta-chi activity diagram.