Quantitative structure-cytotoxicity relationship of newly synthesised trihaloacetylazulenes determined by a semi-empirical molecular-orbital method (PM5).

Background: In order to extend the search for tumour-targeting compounds, this study performed a quantitative structure-activity relationship (QSAR) analysis of 26 newly synthesised trihaloacetylazulenes. Materials and Methods: The value of 50% cytotoxic concentration (CC 50 ) of trihaloacetylazulenes against human oral squamous cell carcinoma (HSC-2, HSC-3, HSC-4) and human promyelocytic leukaemia (HL-60) cell lines was calculated from the dose-response curve by the MTT method. CONFLEX/CAChe PM5 was used for the calculation of 11 physico-chemical features for each compound. Results: When all 26 compounds were analysed together, the CC 50 values correlated well with the dipole moment, the lowest unoccupied molecular orbital energy and the reactivity index, and somewhat with the heat of formation, the stability of hydration and the absolute electron negativity, but not with other features. When these 26 compounds were separated into two groups with or without substituents of the 7-membered ring, the correlation coefficient was increased. When the 26 compounds were separated into a different set of two groups with different halogen atoms in the 5-membered ring, no improvement of correlation coefficient was observed. Conclusion: The present study suggests that appropriate grouping of test compounds may further increase the correlation coefficient. The QSAR approach was useful in the design of azulene compounds that are expected to show higher potency. Quantitative structure-activity relationship (QSAR) represents the quantitative relationship between the structure and the biological (pharmaceutical or toxicological) activity of chemical entities. QSAR analyses are possible, based on previously published data, and provide a powerful tool for predicting the pharmacological potency of structurally related compounds (Figure 1).