Abstract
Eight new thiosemicarbazone derivatives, 6-(1-trifluoroethoxy)pyridine-3-carbaldehyde thiosemicarbazone (1), 6-(4′-fluorophenyl)pyridine-3-carbaldehyde thiosemicarbazone (2), 5-chloro-pyridine-3-carbaldehyde thiosemicarbazone (3), 2-chloro-5-bromo-pyridine-3-carbaldehyde thiosemicarbazone (4), 6-(3′,4′-dimethoxyphenyl)pyridine-3-carbaldehyde thiosemicarbazone (5), 2-chloro-5-fluor-pyridine-3-carbaldehyde thiosemicarbazone, (6), 5-iodo-pyridine-3-carbaldehyde thiosemicarbazone (7), and 6-(3′,5′-dichlorophenyl)pyridine-3-carbaldehyde thiosemicarbazone (8) were synthesized, from the reaction of the corresponding pyridine-3-carbaldehyde with thiosemicarbazide. The synthesized compounds were characterized by ESI-Mass, UV-Vis, IR, and NMR (1H, 13C, 19F) spectroscopic techniques. Molar mass values and spectroscopic data are consistent with the proposed structural formulas. The molecular structure of 7 has been also confirmed by single crystal X-ray diffraction. In the solid state 7 exists in the E conformation about the N2-N3 bond; 7 also presents the E conformation in solution, as evidenced by 1H NMR spectroscopy. The in vitro antitumor activity of the synthesized compounds was studied on six human tumor cell lines: H460 (lung large cell carcinoma), HuTu80 (duodenum adenocarcinoma), DU145 (prostate carcinoma), MCF-7 (breast adenocarcinoma), M-14 (amelanotic melanoma), and HT-29 (colon adenocarcinoma). Furthermore, toxicity studies in 3T3 normal cells were carried out for the prepared compounds. The results were expressed as IC50 and the selectivity index (SI) was calculated. Biological studies revealed that 1 (IC50 = 3.36 to 21.35 μM) displayed the highest antiproliferative activity, as compared to the other tested thiosemicarbazones (IC50 = 40.00 to >582.26 μM) against different types of human tumor cell lines. 1 was found to be about twice as cytotoxic (SI = 1.82) than 5-fluorouracile (5-FU) against the M14 cell line, indicating its efficiency in inhibiting the cell growth even at low concentrations. A slightly less efficient activity was shown by 1 towards the HuTu80 and MCF7 tumor cell lines, as compared to that of 5-FU. Therefore, 1 can be considered as a promising candidate to be used as a pharmacological agent, since it presents significant activity and was found to be more innocuous than the 5-FU anticancer drug against the 3T3 mouse embryo fibroblast cells.
Highlights
We have reported the cytotoxic activity of compounds derived from benzaldehyde, naphthaldehyde, and furan-2-carbaldehyde thiosemicarbazones against different human tumor cell lines [23,24,25]
Compounds 1–8 were tested for their in vitro antiproliferative activity against six human tumor cell lines: H460, HuTu80, DU145, MCF-7, M-14, and HT-29
All reagents and solvents were purchased from Sigma-Aldrich of analytical grade and were used without further purification. e tested human tumor cell lines were H460, HuTu80, DU145, MCF-7, M-14, and HT-29, while the tested non-tumor cell line consisted of BALB/3T3 mouse embryonic fibroblast cells
Summary
Thiosemicarbazones with general formula R1R2CH N-NH-(C S)-NH2 have been attracting the attention of researchers, because of their multifunctional coordination modes to transition metal ions [1, 2], and because of their wide range of biological properties including antibacterial [3,4,5,6], antifungal [7], antimicobacterium tuberculosis [8, 9], and antitumoral [10,11,12,13,14] activity.iosemicarbazones usually react as chelating ligands with metal ions by bonding through the thiocarbonyl sulfur and the azomethine nitrogen atoms [15,16,17]. Thiosemicarbazones and the corresponding coordination compounds have been extensively investigated for their antriproliferative activity against different human tumor cell lines. Us, cytotoxic studies with pyridine thiosemicarbazone derivatives: pyridine-2-carbaldehyde thiosemicarbazone, 2-acetylpyridine- 4-cyclohexyl thiosemicarbazone, and 2formylpyridin-4-N-ethyl-thiosemicarbazone, revealed that these compounds possess higher antiproliferative activity in vitro (IC50 < 0.55 to 4.88 μM) against MCF-7 (human breast cancer cell line), as compared to cisplatin (IC50 = 8.0 μM) [20,21,22]. As a part of our efforts towards the synthesis and structural characterization of new materials containing biorelevant pyridinyl thiosemicarbazones and the understanding of their cytotoxic activity against different human tumor cell lines, the present work describes the synthesis and spectral characterization of eight new pyridine-3-carbaldehyde thiosemicarbazone derivatives. Compounds 1–8 were tested for their in vitro antiproliferative activity against six human tumor cell lines: H460 (lung large cell carcinoma), HuTu80 (duodenum adenocarcinoma), DU145 (prostate carcinoma), MCF-7 (breast adenocarcinoma), M-14 (amelanotic melanoma), and HT-29 (colon adenocarcinoma)
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