Quantum chemical computations on appropriate model systems are used for a rational design of aziridine-based inhibitors of cysteine proteases. They predict that already inductive electron-withdrawing substituents at the aziridine nitrogen strongly accelerate the alkylation step of the inhibition process in neutral and alkaline media, but also for more acidic environments improvements are predicted. With this we generalize previous findings that found similar effects for N-formylated compounds. Furthermore, the new substituents possess the additional advantage that they do not open up reaction pathways other than the nucleophilic ring opening. To verify the hypotheses selected compounds were synthesized and tested. These tests approved the predictions and showed that the corresponding derivatives of aziridine-2,3-dicarboxylate are potent irreversible inhibitors of cysteine proteases. On the basis of measured inhibition data the new inhibitors offer an up to 2,300-fold increase in inhibition potency compared to the unsubstituted inhibitor. Additionally, the kinetics of a selected reaction with 4-methoxy thiophenolate as model thiol were measured in solution to ascertain that the inhibition mechanism is the irreversible alkylation of the cysteine residue of the protease's active site under ring opening of the new inhibitors.