Novel guanidine derivatives as mechanistic scaffolds for anticancer agents: synthesis, characterization, DNA-binding, and computational studies

Cancer continues to be a major global health challenge, necessitating the ongoing development of novel small-molecule therapeutics that can selectively target DNA and disrupt cancer cell proliferation. In this study we report the synthesis and characterization of novel guanidine derivatives (7a-j). Their DNA-binding potential was assessed through electronic absorption spectroscopy, revealing characteristic hypochromic shifts indicative of minor groove-binding interactions with salmon sperm DNA (SS-DNA). Among the series, 4-Me, 4-Br-substituted compound (7i) exhibited the highest binding constant (<i>K</i> _b = 3.49 × 10⁵ ± 0.04 M^-1 at 298 K), comparable to that of the reference groove binder, cabozantinib (<i>K</i> _b = 5.79 × 10⁵ M^-1). The negative Gibbs free energy change (Δ<i>G</i> = -31.61 kJ mol^-1) confirmed the spontaneity and thermodynamic stability of the binding interaction. Molecular docking studies further supported these experimental findings, with compound (7i) displaying a favorable docking score of -8.9 kcal mol^-1 and forming hydrogen bonding and hydrophobic interactions within the DNA minor groove. Additionally, DFT calculations and ADMET predictions provided insights into the electronic features and pharmacokinetic attributes of novel guanidine derivatives (7a-j), establishing DNA binding as a mechanistic foundation and reinforcing their rationale for future evaluation in anticancer drug discovery.