Synthesis, characterization, crystal structures, antitumor activity, and computational study of novel thiosemicarbazone derivatives from thiazol-2/5-carbaldehyde

Hernández W.; Carrasco F.; Vaisberg A.; Spodine E.; Icker M.; Krautscheid H.; Jänke C.; Beyer L.; Yáñez O. · RSC Advances (2026) · DOI: 10.1039/d6ra04078k

Resumen

Twelve new thiazol-carbaldehyde thiosemicarbazone derivatives were synthesized by condensing the thiosemicarbazide derivative with the respective thiazol-2/5-carbaldehyde in methanol. The synthesized compounds were characterized by elemental analysis, ESI-mass spectrometry and FT-IR, 1H, 13C and 19F NMR spectroscopy. Elemental and mass spectrometric data are consistent with the proposed structural formulas. In addition, IR and NMR spectral data evidenced the formation of the (–CN–) imine bond in all the synthesized compounds, which confirms the obtaining of the thiazol-carbaldehyde thiosemicarbazone derivatives. The molecular structures of 1, 2, 7 and 11 were determined by X-ray crystallography. These compounds exhibited an E conformation around the N2–C4, N2–C5, N3–C9 and N3–C6 bonds. The in vitro cytotoxic activity of the synthesized thiosemicarbazones was evaluated against five human tumor cell lines: HuTu80 (duodenum adenocarcinoma), DU145 (prostate carcinoma), MCF-7 (breast adenocarcinoma), M14 (amelanotic melanoma) and HT-29 (colon adenocarcinoma), using the sulforhodamine B assay. Besides, BALB/3T3 cells (mouse fibroblast) were also tested as representative of normal cells. The HuTu80, DU145 and BALB/3T3 cell lines were obtained from ATCC (American Type Culture Collection), while the MCF-7, M-14 and HT-29 cell lines were obtained from NCI (National Cancer Institution). Among the tested human tumor cell lines, compounds 3 and 6 showed greater cytotoxicity (IC50 = 10.58 and 9.63 µM, respectively) than the other tested compounds against the MCF-7 tumor cell line. Compounds 3 and 6 showed similar cytotoxicity in comparison to the reference compound (5-fluorouracil). However, 3 was more innocuous against 3T3 normal cells. Theoretical investigations showed the effect of the substituent groups on the electronic properties of compounds 3 and 6. HOMO–LUMO and global reactivity analyses indicate that 3 and 6 possess higher chemical reactivity and exhibit lower kinetic stability than the reference inhibitor BI2536 of the Polo-like kinase 1. Compound 3 containing the fluorophenyl substituent on the thiazole ring revealed to be a stronger electrophile with a greater tendency to accept electrons from residues present in the PLK1 pocket. Molecular docking suggested that 3 and 6 engage key PLK1 residues through hydrophobic, hydrogen-bonding, and π-stacking interactions while BI2536 provides a broader and more established interaction profile. These findings demonstrate that compounds 3 and 6 have the potential to be considered as promising lead compounds for further investigation. This journal is © The Royal Society of Chemistry, 2026.

Instituciones: Universidad Peruana Cayetano Heredia; Universidad de Lima