Design and Synthesis of Purine–Biphenyl Hybrids: Cytotoxicity, ADMET Analysis and MD Simulation Study

A novel series of purine–biphenyl hybrids was designed and synthesized by linking 2,6-dichloropurine with methyl-2-cyanobiphenyl, aiming to develop cytotoxic agents targeting the Epidermal Growth Factor Receptor (EGFR). Structural diversity was introduced via C6 substitution with different aniline derivatives, affording compounds 4a-4j. In vitro screening against the MCF-7 breast cancer cell line revealed compound 4h (2-CF3) as the most active (IC50 = 19.06 µM), followed by 4d (4-CF3, 2-Br) and 4c (4-F). Structure-activity relationship analysis indicated that electron-withdrawing substituents enhanced cytotoxicity, while unsubstituted and electron-donating derivatives were less active. Molecular docking identified compounds 4h and 4d as the top binders, with binding affinities of −19.6 and −19.2 kcal/mol, respectively, surpassing the reference drug doxorubicin. Molecular dynamics simulations over 100 ns demonstrated stable binding conformations for both compounds, supported by MM/GBSA calculations. Compound 4d maintained favorable binding free energies (−36.7 to −27.5 kcal/mol), while 4h exhibited ΔG binding energies ranging from −30.4 to −49.8 kcal/mol, indicating enhanced interaction strength over time. ADMET predictions further revealed good oral absorption, low toxicity, and favorable drug-likeness for both compounds. These integrated results suggest that compounds 4d and 4h have considerable potency against EGFR.