2D and 3D‐QSAR studies on antiproliferative thiazolidine analogs

Two‐dimensional (2D) and three‐dimensional (3D) quantitative structure–activity relationships (QSARs) of 22 thiazolidine analogs with antiproliferative activity expressed as pIC₅₀, which is defined as the negative value of the logarithm of necessary molar concentration of these compounds to cause 50% growth inhibition against melanoma cell lines WM‐164, have been studied by using a combined method of the DFT, MM2 and statistics for 2D, as well as the comparative molecular field analysis (CoMFA) method for 3D. The established 2D‐QSAR model in training set comprised of random 18 compounds shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient (R = 0.832) and the square of the cross‐validation coefficient (q² = 0.803). The same model was further applied to predict pIC₅₀ values of the four compounds in the test set, and the resulting R reaching 0.784, further confirms that this 2D‐QSAR model has high predictive ability. The 3D‐QSAR model also shows good correlative and predictive capabilities in terms of R² (0.956) and q² (0.615) obtained from CoMFA model. Further, the robustness of the CoMFA model was verified by bootstrapping analysis (100 runs) with R (0.979) and SD_bs (0.056). It is very interesting to find that the results from 2D‐ and 3D‐QSAR analyses accord with each other, and they all show that the steric interaction plays a crucial role in determining the cytotoxicities of the compounds, and that selecting a moderate‐size or appropriate‐hydrophobicity substituent R as well as increasing the negative charges of C₄ on phenyl ring at the same time are advantageous to improving the cytotoxicity. Such results can offer some useful theoretical references for directing the molecular design and understanding the action mechanism of this kind of compound with antiproliferative activity. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008