On the Stability of Zwitterions of Pyridine Sulfonylureas: The Effect of Isosterism, Acidity, and Microsolvation

Abstract

Pyridine sulfonylureas (PSUs) are known to exist in zwitterionic form in the solid phase. For example, torsemide, a diuretic drug, exists in three polymorphic forms: two of them in the zwitterionic state and one in the "partial zwitterionic" state. Initial computational analysis showed that the energy difference between the canonical and the zwitterionic states of a model PSU is very large in the gas phase (∼15 kcal/mol), thus disfavoring the zwitterionic state. In order to understand the apparent dichotomy on the preferred state of PSUs, extensive computational analysis using density functional theory was taken up on a few analogues of PSU. The zwitterionic isomer was less stable than the canonical form in the model PSU, 4-amino-pyridyl-3-sulfonylurea. However, under implicit polar solvent conditions, the zwitterionic and the canonical forms of the model PSU were nearly isoenergetic. Furthermore, microsolvation calculations showed that the zwitterionic model of torsemide is thermodynamically more favorable over the canonical form in the presence of seven water molecules. A combined microsolvation-continuum solvent model showed that the zwitterionic form starts to dominate the canonical form under the influence of four water molecules. Analysis on the intramolecular interactions, the partial atomic charges, the conformational and tautomeric preferences was also carried out, which enabled the rationalization of the formation of stable zwitterionic species in PSUs.

“Release and Catch” Effect of Perfluoroalkylsulfonylimide‐Functionalized Imidazole/Pyridine on Brønsted Acids in Organic Systems

“…Thus, the SO 3 H‐style IL existed in the form of a zwitterion and strong acid with an easy H‐shift from the strong acid to the zwitterion to form the counter‐anion and the SO 3 H group . Dhaked and Bharatam performed a computational analysis that showed, under implicit polar solvent conditions, that the zwitterionic isomer in 4‐amino‐pyridyl‐3‐sulfonylurea was nearly isoenergetic with the canonical form, which was even predominant under the influence of water molecules . The acidic proton probably shifts between the pyridine ring and sulfonylurea group.…”

“…[19] Dhaked and Bharatam performed ac omputational analysist hat showed, under implicit polar solvent conditions, that the zwitterionic isomer in 4-amino-pyridyl-3-sulfonylureaw as nearly isoenergetic with the canonical form, which was even predominant under the influence of water molecules. [20] The acidic proton probably shifts between the pyridine ring and sulfonylureag roup. It was thus possible to transfer TfOH between the zwitterion and the solvent.…”

Electronic structure and conformational analysis of P218: An antimalarial drug candidate

“…This is confirmed from Table in which the relative energy values between C1 and Z3 ; C1 and Z4 are reduced under implicit solvent conditions. Several studies are reported on the possible equilibrium between canonical and zwitterionic structures of amino acids and some important drug like molecules . As discussed in the introduction section, minimum seven water molecules are required to reduce the energy difference between canonical and zwitterionic form of glycine, however, one water molecule is sufficient to achieve the same in the case of arginine.…”

“…The canonical vs . zwitterionic states of amino acids are subjects of extensive study . It was reported that in the presence of seven explicit water molecules the zwitterionic form of glycine becomes more stable than its canonical form .…”

“…[1] The canonical vs. zwitterionic states of amino acids are subjects of extensive study. [32][33][34][35][36][37][38][39][40] It was reported that in the presence of seven explicit water molecules the zwitterionic form of glycine becomes more stable than its canonical form. [41,42] On the other hand it is reported that the complexation of arginine with one water molecule makes the zwitterionic form more stable over the canonical form.…”