Previous studies within our group have yielded a class of cinnamoyl-based competitive reversible inhibitors for tissue transglutaminase (TG2), with values as low as 1.0 μM (compound). However, due to the electrophilic nature of their alkene moiety, this class of inhibitors is susceptible to nucleophilic attack by glutathione, a key element in cellular metabolism and toxicity response. To address this issue, we made several modifications to the inhibitor scaffold, ultimately showing that a bis(triazole) scaffold increased resistance to nucleophilic attack, with compound being the most potent ( = 10 μM). In the process of reducing reactivity, we also prepared a new class of inhibitors, replacing the alkene of with an alkyne, leading to a significant increase in potency for compound ( = 420 nM).
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