Halogenation effects of pheniramines on the complexation with beta-cyclodextrin.

Area of Science:

• Supramolecular Chemistry
• Computational Chemistry
• Medicinal Chemistry

Background:

• Cyclodextrins are widely used in drug formulation to enhance solubility and stability.
• Pheniramine and its halogenated derivatives are common antihistamines.
• Understanding host-guest interactions is crucial for drug design.

Purpose of the Study:

• To investigate the formation and stability of beta-cyclodextrin inclusion complexes with pheniramine and its halogenated derivatives.
• To characterize the influence of phenyl ring halogenation on intermolecular interactions.
• To correlate experimental findings with theoretical calculations.

Main Methods:

• Experimental methods: Fourier transform infrared spectroscopy and Nuclear Magnetic Resonance (NMR) spectroscopy.
• Theoretical methods: ONIOM(B3LYP/6-31G(d):PM3) hybrid method for geometry optimization.
• Natural Bond Orbital (NBO) analysis for electronic delocalization and intermolecular forces.

Main Results:

• Evidence of inclusion complex formation confirmed by FTIR and NMR.
• Apparent binding constants evaluated, showing a stability order: brompheniramine > chlorpheniramine > pheniramine.
• Calculated binding energies and NBO analysis revealed electronic delocalizations as key drivers of binding strength, with S-enantiomers more stable than R-enantiomers.

Conclusions:

• Halogenation of the phenyl ring in pheniramine derivatives significantly enhances binding affinity to beta-cyclodextrin.
• Intermolecular electronic delocalizations are the primary forces governing the stability of these inclusion complexes.
• Computational methods accurately predict experimental observations, providing a valuable tool for future drug design.