Synthesis of 4,6-Diphenyl-3-cyanopyridine Derivatives Based on 3D-QSAR: Unveiling Their Potential as Survivin Protein Inhibitors

Abstract The development of novel and potent Survivin protein inhibitors represents a crucial strategy in anticancer drug discovery. Three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling has proven to be a valuable tool for accelerating the identification of biologically active compounds. In this study, we conducted a 3D-QSAR analysis on a series of 4,6-diphenyl-3-cyanopyridine derivatives synthesized in our laboratory, correlating their structures with A375 cell IC₅₀ values. Guided by 3D contour maps derived from Comparative Molecular Field Analysis (CoMFA, q² = 0.657) and Comparative Molecular Similarity Index Analysis (CoMSIA, q² = 0.709), sixteen novel derivatives were designed and synthesized. Among these, compound D14 demonstrated improved anticancer activity relative to the template molecule 3. Finally, molecular docking, interaction fingerprint analysis, and molecular dynamics simulations were employed to elucidate the binding modes between the 4,6-diphenyl-3-cyanopyridine derivatives and the Survivin protein.