First lepidiline-inspired 1,3-dibenzyl 2-CF₃S-imidazoliums: Design, synthesis and cytotoxic activity study

A series of lepidiline-type 4,5-dimethylimidazolium hexafluorophosphates, functionalized with F atom(s) as well as the CF₃, OCF₃, OCH₃ and SCF₃ groups located either in the central core or placed at benzyl-type N-substituents, was prepared, and the cytotoxicity against selected cancer cell lines was examined. The applied four-step protocol based on condensation of diacetyl monoxime with formaldimines (hexahydro-1,3,5-triazines), one-pot telescopic sulfur-transfer followed by electrophilic trifluoromethylation, and subsequent N-alkylation of the central imidazole ring, enabled access to symmetrical and unsymmetrical products. The counterion metathesis provided crystalline hexafluorophosphates, which were isolated in high overall yield. Analysis of biological activity of the intermediate CF₃S-imidazoles and the corresponding imidazoliums against HeLa, HepG2, and A549 cancer cell lines revealed amplified cytotoxicity of the final salts in comparison to natural lepidiline alkaloids, which is promising in the context of drug discovery.