Synthesis and structural characterization of 18-, 19-, 20- and 22-membered Schiff base macrocycles

The complexation parameters of dipyridamole (Dipy) with β-cyclodextrin (β-CD) were investigated by using several techniques including phase solubility diagrams (PSD), proton nuclear magnetic resonance (¹H-NMR), x-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and molecular mechanical modeling (MM⁺). From the pH-solubility profiles, two basic pK _as at 6.4 and 2.7 were estimated. The linear correlation of the free energy of Dipy/β-CD complex formation (ΔG ₁₁) with the corresponding free energy of inherent Dipy aqueous solubility (ΔG _So), obtained from the linear variation of ln K ₁₁ with that of the inherent Dipy solubility (ln S _o) at different pHs and ionic strengths, was used to measure the contribution of the hydrophobic character of Dipy to include into the hydrophobic β-CD cavity. Complex formation of Dipy was driven by favorable enthalpy (ΔH° = ?14.8 kJ/mol) and entropy (ΔS° = 31.9 J/mol K) factors. ¹H-NMR and molecular mechanical modeling studies indicate the formation of different isomeric 1:1 and 1:2 complexes, where both the piperidine and diethanolamine moieties get separately included into the β-CD cavity. Molecular mechanical modeling computations indicate that the dominant driving force for complexation is Van der Waals with lower contribution from electrostatic interactions. ¹H-NMR and XRPD, DSC, SEM studies of isolated solid complexes indicate the formation of inclusion complexes in aqueous solution.