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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.