Thiosemicarbazone-based compounds have attracted significant attention in recent years due to their potential as inhibitors of cancer cell proliferation. They not only exhibit strong antiproliferative effects but also possess antioxidant properties that are crucial in combating oxidative stress linked to cancer progression. This review highlights specific compounds that not only exhibit significantly higher antiproliferative activities but also demonstrate lower toxicity compared to traditional chemotherapy agents. This is important because it suggests that these compounds could provide better treatment options while reducing the side effects often associated with chemotherapy. A detailed analysis of the structure–activity relationships (SARs) reveals that the unique structural features of these compounds play a crucial role in their enhanced effectiveness. Understanding which molecular characteristics contribute to improved activity will be key for future compound design. The findings from this study emphasize the need for further exploration and development of these novel agents. By investigating their biological mechanisms and optimizing their structures, researchers can improve cancer treatment strategies, providing safer and more effective options for patients. Despite substantial previous research on thiosemicarbazones and isothiosemicarbazones, the field still holds many unknowns and opportunities for discovery. Studying coordination chemistry with 3d metal ions and strategically modifying their inner structures may lead to new compounds with promising biological activities and selectivity. Overall, exploring thiosemicarbazones and isothiosemicarbazones as innovative pharmacological agents against cancer could unlock their full potential, significantly enhancing cancer treatment protocols and improving patient survival rates.

A series of zinc(II) ([Zn(H₂O)(L)Cl] (1)), copper (II) ([Cu(L)Cl] (2), [Cu(L)Br] (3), [Cu₂(L)₂(CH₃COO)₂]·4H₂O (4)), nickel(II) ([Ni(HL)₂]Cl₂·H₂O (5)), and cobalt(III) ([Co(L)₂]Cl (6)) complexes were obtained with 2‐formylpyridine N⁴‐allylthiosemicarbazone (HL). In addition another two thiosemicarbazones (3‐formylpyridine N⁴‐allylthiosemicarbazone (HL^a) and 4‐formylpyridine N⁴‐allylthiosemicarbazone (HL^b)) have been obtained. The synthesized thiosemicarbazones have been studied using ¹H and ¹³C NMR spectroscopy, IR spectroscopy, and X‐ray diffraction analysis. The composition and structure of complexes were studied using elemental analysis, IR and UV‐Vis spectroscopies, molar conductivity, and magnetic susceptibility measurements. Single crystal X‐ray diffraction analysis elucidated the structure of thiosemicarbazones HL, HL^a, and HL^b, as well as complexes 4 and 5. The antiproliferative properties of these compounds toward a series of cancer cell lines (HL‐60, HeLa, BxPC‐3, RD) and a normal cell line (MDCK) have been investigated. The nickel complex shows high selectivity (SI > 1000) toward HL‐60 cell line and is the least toxic. The zinc complex shows the highest selectivity toward RD cell line (SI = 640). The copper complexes (2–4) are the most active molecular inhibitors of proliferation of cancer cells, but exhibit not such a high selectivity and are significantly more toxic. Zinc and copper complexes manifest high antibacterial activity. It was found that calculated at B3LYP level of theory different reactivity descriptors of studied compounds strongly correlate with their biological activity.

The eleven new copper(II) and nickel(II) coordination compounds [Cu(L)Br]₂ (1), [Cu(L)Cl] (2), [Cu(L)NO₃] (3), [Ni(L)Cl] (4), [Ni(HL)₂](NO₃)₂ (5), and [Cu(A)(L)]NO₃, where A is 1,10-phenanthroline (6), 2,2′-bipyridine (7), 3,4-dimethylpyridine (8), 3-methylpyridine (9), pyridine (10) and imidazole (11) were synthesized with 3-(morpholin-4-yl)propane-2,3-dione 4-allylthiosemicarbazone (HL). The new thiosemicarbazone was characterized by NMR and FTIR spectroscopy. All the coordination compounds were characterized by elemental analysis and FTIR spectroscopy. Also, the crystal structures of HL and complexes 1, 6, 7, and 11 were determined using single-crystal X-ray diffraction analysis. Complex 1 has a dimeric molecular structure with two bromide bridging ligands, while 6, 7, and 11 are ionic compounds and comprise monomeric complex cations. The studied complexes manifest antibacterial and antifungal activities and also have an antiradical activity that, in many cases, surpasses the activity of trolox, which is used as a standard antioxidant in medicine. Copper complexes 1–3 have very weak antiradical properties (IC₅₀ > 100 µM), but nickel complexes 4–5 are strong antiradicals with IC₅₀ values lower than that of trolox. The mixed ligand copper complexes with additional ligand of N-heteroaromatic base are superior to complexes without these additional ligands. They are 1.4–5 times more active than trolox.

Ten coordination compounds, [Cu(L¹)Cl] (C1), [Cu(L¹)NO₃] (C2), [Cu(L²)Cl] (C3), [Cu(L²)NO₃] (C4), [Cu(L³)Cl] (C5), [Cu(L³)NO₃] (C6), [Cu(L⁴)NO₃] (C7), [Cu(L⁴)Cl] (C8), [Cu(L⁵)Cl] (C9), and [Cu(L⁵)NO₃] (C10), containing pyridine derivatives of N⁴-methoxyphenyl-thiosemicarbazones were synthesized and characterized. The molecular structure of four compounds was investigated using single crystal X-ray diffraction. Spectral analysis techniques such as FT-IR, ¹H NMR, ¹³C NMR, elemental analysis, and molar conductivity were used for all the synthesized compounds. The tested synthesized compounds were evaluated for their anticancer activity and selectivity against a variety of cancer cell lines, including HL-60, LNCaP, MCF-7, HepG-2, K-562, HeLa, BxPC-3, RD, and MDCK normal cell line. Most compounds demonstrated selective anticancer activity superior to doxorubicin. Notably, all ligands showed high antiproliferative activity against HL-60 cells, with IC₅₀ values between 0.01 and 0.06 µM and a selectivity index as high as 5000. Coordination of copper(II) with ligands HL¹ and HL³ notably enhanced antiproliferative activity, lowering the IC₅₀ to 0.03 µM. Additionally, the antioxidant activity of these compounds was assessed, revealing that all tested ligands and most coordination compounds exhibited greater antioxidant activity compared to Trolox, with some ligands showing activity up to 12.3 times higher. Toxicity studies on Daphnia magna indicated low toxicity for the ligands, generally less than doxorubicin, with LC₅₀ values ranging from 13 to 90 µM, suggesting moderate toxicity. Conversely, the coordination complexes were more toxic, with LC₅₀ values between 0.5 and 13 µM.

The six new copper(II) coordination compounds [Cu(HL¹)Cl₂] (1), [Cu(HL¹)Br₂] (2), [Cu(H₂O)(L¹)(CH₃COO)]·1.75H₂O (3), [Cu(HL²)Cl₂] (4), [Cu(HL²)Br₂] (5), [Cu(H₂O)(L²)(CH₃COO)] (6) were synthesized with 2-formyl- and 2-acetylpyridine N⁴,S-diallylisothiosemicarbazones (HL¹ and HL²). The new isothiosemicarbazones were characterized by NMR, FTIR spectroscopy, and X-ray crystallography ([H₂L²]I). All copper(II) coordination compounds were characterized by elemental analysis, FTIR spectroscopy, and molar conductivity of their 1mM methanol solutions. Furthermore, the crystal structure of complex 3 was determined using single-crystal X-ray diffraction analysis. The studied complexes manifest antibacterial and antifungal activities, that in many cases are close to the activity of medical drugs used in this area, and in some cases even exceed them. The complexes 4 and 5 showed the highest indexes of selectivity (280 and 154) and high antiproliferative activity against BxPC-3 cell lines that surpass the activity of Doxorubicin. The complexes 1–3 also manifest antioxidant activities against cation radicals ABTS^•+ that are close to that of trolox, the antioxidant agent used in medicine.