Tissue transglutaminase (TG2) is a multifunctional protein that can catalyze the cross-linking between proteins, and function as a G-protein. TG2's unregulated behaviour has been associated with fibrosis, celiac disease and cancer metastasis. Recently, small molecule irreversible inhibitors have been designed, bearing an electrophilic warhead that can react with the catalytic cysteine, abolishing TG2's catalytic and G-protein capabilities. Several research groups have converged on inhibitors comprising piperazine scaffolds, but no structure-activity relationships (SAR) of the piperazine core have been reported. In this study we synthesize a series of inhibitors with various diamino linkers, to understand what structural requirements are necessary for the core to help align the terminal acrylamide warhead in the optimal position. Kinetic evaluation using an in vitro biochemical assay provided the kinetic parameters k