Computational Design and Synthesis of Phthalimide Derivatives as TGF-β Pathway Inhibitors for Cancer Therapeutics

Background: This study investigates the synthesis and pharmacological potential of N-substituted isoindoline-1,3-dione (phthalimide) derivatives. Using the M06 meta-GGA hybrid functional with a polarized 6-311G(d,p) basis set, computational evaluations assessed their impact on apoptosis modulation in colon cancer cells. Molecular docking studies targeted the TGF-β protein (PDB: 1RW8) at the ALK5 binding site. On this study fourteen molecules were evaluated (P1–P14) and six (P1, P3, P4, P5, P7, and P13) demonstrated promising binding values. Methods: from the fourteen studied compounds five compounds (P2, P4, P7, P10, and P11) were successfully synthesized and fully characterized. The reactions were monitored via TLC and HPLC confirming high-purity compounds. Functional groups were identified through FTIR and structural characterization was supported by NMR analyses. Results: Density functional theory calculations and docking simulations allowed to classified the compounds as potential ALK5 inhibitors. Synthesized derivatives were developed in yields from 85 to 99% and showed better binding affinities than Capecitabine (−6.95 kcal/mol) used as control compound, with P7 (5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl 2-(1,3-dioxoisoindolin-2-yl) acetate) leading the group with a binding energy of −12.28 kcal/mol. Other synthesized compounds also exhibited significant affinities: P4 (−11.42 kcal/mol), P10 (−8.99 kcal/mol), P11 (−7.50 kcal/mol), and P2 (−7.22 kcal/mol). Conclusions: Integrating computational insights with experimental validation highlights the therapeutic potential of phthalimide derivatives, particularly P7. The study underscores a rigorous approach to identifying promising candidates for anticancer therapeutics, warranting further exploration.