α-Aminophosphonate and their related derivatives have garnered significant attention as a result of their use in many
biological and industrial applications, particularly in the fields of materials science. This research described synthesis and characterization of novel α-aminophosphonate derivatives (ES1-ES4) based on poly(p-hydroxystyrene). The synthesis was achieved by chemically modification of poly(p-hydroxystyrene) (PHS) with triphenylphosphite and various aldehydes (vanillin, N,N'-dimethylaminobenzaldhyde, p-chlorobenzaldhyde, and 3,4,5-trimethoxybenzaldhyde). The chemical structures were confirmed using FT-IR, 1H, 13C and 31P-NMR besides the thermal analysis techniques. A significant increase in molecular weight and radius of gyration were observed following functionalization, as evidenced by static laser light dispersion. The degree of functionalization (DoF) ranged from 71.5 to 80.06. The electronic properties and physical characteristics of these derivatives were elucidated through computational studies that employed DFT simulations. These studies revealed significant changes in the electron density distribution, electrostatic potential, and key polymeric properties, such as optical characteristics, mechanical strength, and glass transition temperature. Based on antimicrobial investigation, ES1 and ES4 showed potent inhibition against gram-positive bacteria and Candida albicans, indicating broad-spectrum activity. With a selectivity index of 1.50–1.72, cytotoxicity evaluations demonstrated that derivatives coded ES2, ES3, and ES4 exhibited reduced toxicity towards normal lung fibroblasts, recording IC50 of 181.37, 193.38 and 203.95 μg/ mL, respectively. On the other hand, higher selective toxicity against HepG2 liver cancer cells with IC50 values: 118.27, 121.75 and 121.18 μg/mL. These results demonstrated that α-aminophosphonate hybrid polymers have great promise as antibacterial and preliminary anticancer potential against HepG2 cells, while maintaining moderate safety toward normal fibroblasts at lower concentrations.