Application of Semiempirical Method to Estimate Cytotoxicity of 5-Trifluoromethyloxazole Derivatives

Objective: Although 5-trifluoromethyloxazole derivatives have shown the anti-inflammatory activity due to the inhibition of COX-2, and possible potentiation by the presence of trifluoromethyl group in the molecule, the cytotoxic study of this group of compounds especially against oral tumor cells has been limited. We have published the structure-activity relationship (QSAR) for many natural and synthetic low molecular weight compounds, using semiempirical methed (CAChe/PM3). We investigated here the relative cytotoxic activity of twelve 5-trifluoromethyloxazole derivatives against human oral squamous cell carcinoma (HSC-2, HSC-3, HSC-4) and human promyelocytic leukemia (HL-60) cell lines, and normal human oral cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast), and then confirmed the QSAR between their physico-chemical properties and cytotoxic activity by updated semiempirical methed (CONFLEX/PM3). Methods: All cells were cultured in DMEM supplemented with 10% FBS. The dose-response curve was used to determine the 50% cytotoxic concentration (CC₅₀), and CONFLEX was used for the determination of the most stable structure for each compound. CAChe work system 4.9 was used for the calculation of the following physico-chemical descriptors in each compound: heat of formation, stability of hydration, dipole moment, electron affinity, ionization potential, log P, HOMO energy, LUMO energy, HOMO minus LUMO, absolute hardness, absolute electron negativity and reactivity index. Results: The CC₅₀ did not show the relationship with the heat of formation, stability of hydration, dipole moment, absolute electron negativity, molecular weight, nor molecular length (r²=0.07-0.36), while it showed the relationship between the ionization potential, electron affinity, log P, HOMO energy, LUMO energy, especially HOMO-LUMO, absolute hardness, or reactivity index (r²=0.75-0.86). When the CC₅₀ was plotted vs. log P, parabolic curve was produced with the bottom (maximum cytotoxicity) at 4.6. Conclusion: This QSAR approach is useful to design more active derivatives with similar structures.