Herein we report the synthesis and the evaluation of eight novel compounds as irreversible inhibitors of transglutaminase (TGase). These compounds are based on a minimal peptidic scaffold shown previously [Chem. Biol.2005, 12, 469-475] to confer affinity for the TGase active site and bear electrophilic groups such as alpha,beta-unsaturated amide, chloroacetamide or maleimide; their general structure being Cbz-Phe-spacer-electrophile. The affinity conferred by the Cbz-Phe scaffold was determined by comparison to N-propylacrylamide and the length of the spacer was also varied to evaluate its importance. The inhibitory efficiencies (k(inact)/K(I)) of these compounds vary up to 10(5)M(-1)min(-1), among the highest reported for derivatives based on this simple Cbz-Phe peptidic scaffold.