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This study investigates topoisomerase I and II enzyme inhibition by novel Pd(II) complexes. TSC represents the chelating ligand thiosemicarbazone, which is modified at its 4(N)‐nitrogen terminal position with substituents such as C2H5, CH3, and H. PR3 represents the triphenylphosphine ligand, with positional variations including para substituents H, F, OCH3, and CH3. The aim is to establish a correlation between these molecular variations and cytotoxicity. In particular, the compounds show promising cytotoxicity against MDA‐MB‐231 and A549 tumor cell lines, especially those with H substitution at the terminal position 4(N) of TSC and H and F in the triphenylphosphine. The results suggest that a smaller molecular volume of ligand substituents may enhance the cytotoxic effects. The inhibitory potential of the complexes against DNA topoisomerase enzymes was investigated. The IC₅₀ values of the most promising complexes strongly inhibit TOPOIIα and TOPOIβ, suggesting these enzymes as primary targets. These complexes exhibited significantly lower IC₅₀ values (4.32–4.88 μM) compared to cisplatin (10.2 μM) against MDA‐MB‐231 cells, indicating a distinct mode of action. However, it is noteworthy that the complexes did not inhibit the action of DNA topoisomerase IIβ, suggesting selectivity against specific isoforms of DNA topoisomerase II that act as catalytic inhibitors. [ABSTRACT FROM AUTHOR]

• Synthesis and thorough characterization of novel palladium(II) complexes. • Complexes exhibit remarkably high cytotoxicity, surpassing the activity of cisplatin by more than 300 times. • Interaction assays with biomolecules DNA, HSA, topoisomerase, and cathepsin B. • Complexes have shown the ability to inhibit the action of topoisomerase IB and cathepsin B enzymes. This research presents the synthesis, characterization, anticancer activity, and investigation of biological targets of three new palladium (II) complexes. The compounds were characterized by spectroscopies techniques (UV-Vis, NMR, and IR), elemental analysis, mass spectrometry, and one for monocrystal X-ray diffraction. The cytotoxic activity of the complexes against two cell lines, A2780cis (cisplatin resistance ovarian tumor cell line) and MRC-5 (non-tumor lung cell), was evaluated. The in vitro cytotoxicity assays using the MTT method revealed a significant cytotoxic activity of the palladium complexes against the evaluated cell lines, highlighting the resistance tumor cell line, A2780cis. Also, DNA interaction studies suggested that the compounds either do not interact, or interact weakly with DNA via groove and/or electrostatically. The interaction assay demonstrated that the compounds can weakly to moderately bind to the HSA biomolecule through electrostatic or van der Waals forces. In addition, agarose gel electrophoresis assays indicated that the complexes could not inhibit the action of the enzyme, topoisomerase II alpha. Nonetheless, the complexes demonstrated a promising target against topoisomerase I beta by promoting its inhibition. Finally, fluorescence studies revealed the capacity of irreversible inhibition of the complexes against the enzyme, cathepsin B. 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) antioxidant assay did not show significant scavenging of DPPH radical. The results showed that the proposed structural features generate compounds of high cytotoxicity that can inhibit the action of cathepsin B and topoisomerase I beta. [Display omitted] [ABSTRACT FROM AUTHOR]