2D/3D-QSAR Studies of [1,2,4]Triazolo[1,5-a]pridinylpyridine Derivatives as Potent Anticancer Agents

By using a combined method of density functional theory (DFT), molecular mechanics (MM2) and statistics for two-dimensional (2D), as well as the comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods for three-dimensional (3D), theoretical studies on 2D/3D quantitative structure-activity relationships (QSAR) of 22 novel compounds of [1,2,4]triazolo[1,5-a] pyridinylpyridines acting as PI3K inhibitors against the human colon carcinoma cell line (HCT-116) have been performed. Both the 2D- and 3D-QSAR models established from the random 18 compounds in training set show significant statistical quality and satisfactory predictive ability (R-2 = 0.821, q(2) = 0.773 for 2D-QSAR, R-2 = 0.966, q(2) = 0.668 for CoMFA, R-2 = 0.979, q(2) = 0.753 for CoMSIA). The combined 2D- and 3D-QSAR studies suggest that the moderate-size, hydrophilic and electron-withdrawing group at R-1 position, the bulky and hydrophobic group at R-2 position, and the minor, hydrophobic, H-bond donor and electron-donating group at R-3 position would enhance the anticancer activities. These obtained results help to insight into the action mechanism, and will serve as a basis for the design of new potent anticancer agents.