Protonation behaviour of N,N′-piperazine-dipropionic acid

Abstract

The overall protonation constants of N,N′-piperazine-dipropionic acid (PDPA) were calculated with SUPERQUAD and PSE-QUAD computer programs, at 25 and 37°C and an ionic strength of 0.1 mol dm -3 (KCl). There is a good agreement between the values calculated with the two programs. The obtained values were checked by a simulation titration curve and by the protonation (observed and calculated) curves for C L = 2.0716 mmol dm -3 at 25°C. A two-step deprotonation mechanism is proposed. In the first step the deprotonation occurs to the carboxyl group and in the second step it is the nitrogen atom of the piperazine ring which undergoes deprotonation. To cite this article: C.

Development of New Cyclic Plasmin Inhibitors with Excellent Potency and Selectivity

“…Inhibitors 4 and 8 were docked into the active site of plasmin using FlexX considering different protonation states of the piperazine moiety in the linker segment. In previous experimental studies with N,N′-bisalkylated piperazine derivatives, like N,N′piperazine-dicarbonic acid, 47 N,N′-piperazine-diacetic acid, 48 and N,N′-dimethylpiperazine, 49 it was found that only one of the nitrogens is protonated at physiological pH. Additional pK a calculations with 3,3′-(piperazine-1,4-diyl)bis(N-phenylpropanamide), which is identical to the linker segment of inhibitor 8, were performed with the Marvin Suite 50 and also provided a singly protonated piperazine as major microspecies at physiological pH 7.4 and also at pH 8.0, as used for the kinetic measurements (calculated pK a values of 8.54 and 3.01 for the nitrogens).…”