To further confirm that the observed scaffold effects were not exclusively due to changes in reactivity, we selected a few compounds for determination of the rate of inactivation kinact, binding constant KI (Figure ), and covalent efficiency (kinact/KI) with the phosphatase HePTP. Phenyl chloroacetamide (compound 16), which features a simple scaffold and has low reactivity against GSH and TNB 2-, shows low kinact and high KI (weak binding), contributing to the low covalent efficiency. On the other hand, the benzothiazole-derived chloroacetamide (compound 74), a potent inhibitor of HePTP with high intrinsic reactivity, shows the expected high kinact and high covalent efficiency. Notably, while compound 37 shows a low kinact similar to compound 16, it also has high covalent efficiency arising from a lower KI. These data show how changes in scaffold modulate both kinact and KI and illustrate the potential to optimize scaffolds for tighter binding to achieve high covalent efficiency without excessive reactivity.