Three-dimensional quantitative structure–activity relationship studies on novel series of benzotriazine based compounds acting as Src inhibitors using CoMFA and CoMSIA Original Research Article

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of benzotriazine derivatives, as Src inhibitors. Ligand molecular superimposition on the template structure was performed by database alignment method. The statistically significant model was established of 72 molecules, which were validated by a test set of six compounds. The CoMFA model yielded a q2 = 0.526, non cross-validated R2 of 0.781, F value of 88.132, bootstrapped R2 of 0.831, standard error of prediction = 0.587, and standard error of estimate = 0.351 while the CoMSIA model yielded the best predictive model with a q2 = 0.647, non cross-validated R2 of 0.895, F value of 115.906, bootstrapped R2 of 0.953, standard error of prediction = 0.519, and standard error of estimate = 0.178. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. Results indicate that small steric volumes in the hydrophobic region, electron-withdrawing groups next to the aryl linker region, and atoms close to the solvent accessible region increase the Src inhibitory activity of the compounds. In fact, adding substituents at positions 5, 6, and 8 of the benzotriazine nucleus were generated new compounds having a higher predicted activity. The data generated from the present study will further help to design novel, potent, and selective Src inhibitors as anticancer therapeutic agents.