Quantitative structure-cytotoxicity relationship analysis of 5-trifluoromethyloxazole derivatives by a semiempirical molecular-orbital method with the concept of absolute hardness.

The most stable conformation of twelve 5-trifluoromethyloxazole derivatives was calculated by CONFLEX 5. The optimized structure was determined by CAChe Worksystem 4.9 PM3 method, in the presence (COSMO) or absence (non-COSMO) of water. Higher correlation coefficients for all descriptors were found under COSMO, as compared with non-COSMO conditions. Good correlation was found between the cytotoxicity of these compounds and the electron affinity, ionization potential, highest occupied molecular orbital energy (E(HOMO)), lowest unoccupied molecular orbital energy (E(LUMO)), absolute hardness (eta) and reactivity index (omega). On the other hand, there was generally no clear-cut correlation between CC50 and the heat of formation, stability of hydration, dipole moment, absolute electron negativity (chi), molecular weight, maximum length of molecule, with some exceptions. The cytotoxic activity of 5-trifluoromethyloxazole derivatives became maximum at log p = 4.6. The concept of absolute hardness is applicable in estimating the cytotoxicity of 5-trifluoromethyloxazoles, using an eta-chi activity diagram.