Synthesis and biological evaluation of 2-benzoylpyridine thiosemicarbazones in a dimeric system: Structure–activity relationship studies on their anti-proliferative and iron chelation efficacy

Thiosemicarbazone chelators represent an exciting class of biologically active compounds that show great potential as anti-tumor agents. Our previous studies demonstrated the potent anti-tumor activity of the 2′-benzoylpyridine thiosemicarbazone series. While extensive studies have been performed on monomeric thiosemicarbazone compounds, dimeric thiosemicarbazone chelators have received comparatively less attention. Thus, it was of interest to investigate the anti-proliferative activity and iron chelation efficacy of dimeric thiosemicarbazones. Two classes of dimeric thiosemicarbazones were designed and synthesized. The first class consisted of two benzoylpyridine-based thiosemicarbazone units connected via a hexane or dodecane alkyl bridge, while the second class of dimer consisted of two thiosemicarbazones attached to a 2,6-dibenzoylpyridine core. These dimeric ligands demonstrated greater anti-proliferative activity than the clinically used iron chelator, desferrioxamine. This study highlights the importance of optimal lipophilicity as a factor influencing the cytotoxicity and iron chelation efficacy of these chelators.

Graphical abstractWhile monomeric thiosemicarbazones have been extensively studied as anti-tumor agents, their dimers have received little attention. The anti-proliferative and iron chelation efficacy of novel dimeric thiosemicarbazones have been examined. Dimers demonstrated greater anti-proliferative activity than desferrioxamine. Lipophilicity was crucial in influencing cytotoxicity and iron chelation efficacy.Figure optionsDownload full-size imageDownload as PowerPoint slide