Synthesis and Cytotoxic Activity of Lepidilines A-D: Comparison with Some 4,5-Diphenyl Analogues and Related Imidazole-2-thiones

A straightforward access to 2-unsubstituted imidazole N-oxides with subsequent deoxygenation by treatment with Raney-nickel followed by N-benzylation opens up a convenient route to lepidilines A and C. Both imidazolium salts were used to generate in situ the corresponding imidazol-2-ylidenes, which smoothly reacted with elemental sulfur, yielding imidazole-2-thiones. These reactions were performed either under classical conditions in pyridine solutions or mechanochemically using solid Cs2CO3 as a base. The structure of lepidiline C was unambiguously confirmed by X-ray analysis of its hexafluorophosphate. An analogous protocol toward lepidilines B and D and their 4,5-diphenyl analogues is less efficient due to observed instability of the key precursors, i.e., the respective 2-methylimidazole N-oxides. Comparison of cytotoxic activity against HL-60 and MCF-7 cell lines of all lepidilines, as well as their selected structural analogues (e.g., 4,5-diphenyl derivatives and PF6 salts), revealed slightly more potent activity of the 2-methylated series, irrespectively of the type of counterion present in the imidazolium salt. Remarkably, the well-known 1,3-diadamantylimidazolium bromide (the Arduengo salt), known as the precursor of the first, shelf-stable NHC representative, and its adamantyloxy analogue displayed the most significant cytotoxic activity in the studied series.

Automated summary

A synthetic route to lepidilines A and C was developed by synthesizing 2-unsubstituted imidazole N-oxides and converting them into the target compounds. The 2-methylated series displayed slightly higher cytotoxic activity, regardless of the counterion type. The 1,3-diadamantylimidazolium bromide and its adamantyloxy analogue showed the most significant cytotoxic activity in the series studied.