2D and 3D-QSAR/CoMSIA Comparative Study On a Series of Thiazole Derivatives as SDHI Inhibitors

A database includes compounds based on thiazole derivatives having values of Succinate dehydrogenase inhibitors against S. sclerotiorum (ssSDH) pEC50 was used to develop a structure-activity relationship using 2D and 3D-QSAR methods. The data set used was randomly distributed into 80% as a learning set and 20% to assess the external prediction of the selected models (test set). the reliability and the predictive power of the established models were examined by various methods of internal validation, external validation, and randomized Y test. To detect outliers, the applicability domain was used using the Williams plot.The 2D-QSAR results revealed that the best 2D-QSAR model was established using the multiple linear regression method (MLR) (giving R²= 0.80 and Q²= 0.63), and the partial least squares regression method (PLS) (giving R² = 0.78 and Q² = 0.64), with four descriptors: J, Log P, NRB and MD. These models have successfully passed all external and internal validation criteria.The 3D-QSAR results show that the best model selected using the molecular field analysis method (CoMSIA), giving R² = 0.957, Q² = 0.614, and R²test = 0.80. The analysis of the CoMSIA contour maps shows the nature and the position of certain structural indicators important for the improvement of the studied biological activity such as the steric and electrostatic and hydrophobic substituents, as well as the substitutes of hydrogen bonds donors. These results will also be useful for the development of new thiazole derivatives with very high pEC50 values