Terephthaloyl-based amide-linked derivatives and polymeric networks with selective cytotoxicity: In vitro evaluation, Molecular docking, Molecular dynamics, and DFT insights

Cancer remains a major global health challenge, emphasizing the need for new therapeutic candidates with improved selectivity toward malignant cells and reduced toxicity toward normal cells. In this study, four terephthaloyl-based amide-linked derivatives and polymeric Materials, designated as compounds (1-4), were synthesized through the reaction of terephthaloyl dichloride with hydrazine, diamine, and mono-amino aromatic precursors. Based on the synthetic routes, compounds (3) and (4) are assigned as discrete N,N'-bis-substituted terephthalamide derivatives, whereas compounds (1) and (2) are described as amide-linked polymeric Materials. The formation of amide/acylhydrazide-containing structures was supported by FT-IR analysis through the disappearance or marked reduction of acyl chloride absorptions and the appearance of characteristic amide I-III bands. The structural assignment was further supported by available NMR, mass spectrometry, elemental analysis, purification procedures, and comparative FT-IR spectra of the starting Materials and final products. SEM analysis revealed distinct external morphologies, including a sponge-like honeycomb morphology for compound (1), aggregated or compact textures for compounds (2) and (3), and a fine granular surface for compound (4). The in vitro cytotoxic activity was evaluated using the neutral red uptake assay against PC-3 prostate Cancer and MCF-7 breast Cancer cell lines, while MDCK cells were used as a normal cell model to estimate selectivity. Among the synthesized derivatives, compound (3) exhibited the most potent activity against PC-3 cells, with an IC₅₀ value of 15.7 μg/mL after 48 h and a selectivity index of 3.0, indicating preferential cytotoxicity toward Cancer cells. Compound (2) showed moderate activity against PC-3 cells, whereas compounds (1) and (4) exhibited no significant cytotoxic activity within the tested concentration range. Molecular docking studies against selected cancer-related targets supported the experimental trend, with compound (3) showing favorable binding interactions against PDB ID: 1M17, PDB ID: 4HDQ, and PDB ID: 2ELF through hydrogen bonding, polar contacts, hydrophobic interactions, and multipoint residue anchoring. Molecular dynamics simulations further supported the relative stability of the compound 3-protein complexes, as indicated by stable RMSD profiles, reduced binding-site flexibility, favorable compactness, controlled solvent exposure, and persistent residue contacts compared with the Other derivatives. Conceptual DFT calculations provided complementary electronic-structure insight. Compound (2) displayed the smallest HOMO-LUMO energy gap, indicating higher electronic responsiveness, while compound (3) exhibited the highest electronegativity and electrophilicity values, suggesting stronger electron-accepting character. Mulliken charge analysis also indicated multiple electron-rich carbonyl and amide centers in compound (3), which may contribute to stronger polar and hydrogen-bonding interactions with biomolecular targets. Overall, compound (3) emerged as the most promising scaffold and warrants further mechanistic investigation to validate its Anticancer potential.