Synthesis, characterization, crystal structures, antitumor activity, and computational study of novel...

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 (-C[double bond, length as m-dash]N-) 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.