Design, Synthesis, and Characterization of Novel Cyclotriphosphazene Derivatives Bearing Triazole and Quinoline Moieties: Molecular Docking with Human Serum Albumin and Toxicity Properties

In this study, novel tetra- and di-substituted cyclotriphosphazene derivatives (5-8) were designed, synthesized, and characterized by mass, FT-IR, and NMR (1H, 13C, and 31P) spectroscopies. An organic–inorganic hybridization strategy was employed to design the target compounds. A three-step synthetic route, consisting of nucleophilic substitution and click reactions, was used to construct the desired derivatives. As a result, cyclotriphosphazene-based compounds bearing both triazole and quinoline heterocyclic moieties on the phosphazene core were successfully obtained. Molecular docking studies evaluated the interactions of the synthesized compounds with Human Serum Albumin (HSA), and toxicity properties were predicted with ProTox 3.0. The binding energies of compounds 5, 6, 7, and 8 to HSA were -10.5, -10.9, -13.5, and -14.1 kcal/mol, respectively, and these compounds showed stronger binding than the co-crystallized ligand, warfarin (-10.0 kcal/mol). According to ProTox 3.0, the estimated oral toxic dose was found to be 10,000 mg/kg for compounds 5 and 6, while 1,000 mg/kg for compounds 7 and 8, respectively. The GHS toxicity class is VI for compounds 5 and 6 and IV for compounds 7 and 8, indicating low to moderate acute oral toxicity.