Molecules bearing four, five, and six-membered nitrogen heterocycles such as β-lactams, pyrroles, indoles, and pyridine are important motifs in pharmaceutically relevant molecules. Recently, our group has developed a two-step synthesis to access the rarely studied diazacyclobutene motif via a formal [2+2] cycloaddition between phenyl-triazolinedione and electron-rich thioalkynes. Subsequently, we have continued studying this motif with the objective of expanding the substrate scope. Namely, we have developed a telescoped oxidation/cycloaddition protocol that allows for structural variability in the triazolinedione component. We have also begun to explore the ability of other electron rich alkynes such as ynamide derivatives to engage in the cycloaddition. Preliminary biological evaluation of the scaffold suggests that the diazacyclobutene exhibit potent cytotoxicity against eukaryotic pathogens including <i>Trypanosoma brucei </i>and <i>Trichomonas vaginalis</i>. Prior to our efforts, there were no recorded biological evaluations of these molecules in any sense. This presentation will describe the synthetic efforts to expand the scope of the cycloaddition leading to stable diazacyclobutenes as well as structure-activity relationship evaluations of the motif against medically relevant parasites.

Expansion of the rare diazacyclobutene motif

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