Supramolecular complexes of dihydroazolopyrimidines with macrocyclic receptors: synthesis, rapid analysis, and evaluation

One of the main challenges limiting the medical use of dihydroazolopyrimidine derivatives is their poor water solubility. However, this problem can be significantly reduced by binding to supramolecular receptors. In this study, we investigated the complexation of ethyl 5,7-dimethyl-4,7-dihydrotetrazolo[1,5- a ]pyrimidine-6-carboxylate (DHP1) and ethyl 5-methyl-4,7-dihydro-[1,2,4]triazolo[1,5- a ]pyrimidine-6-carboxylate (DHP2) with macrocyclic receptors: cucurbit[7]uril (CB7), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), and their modified derivatives, per-6-[(2-hydroxyethyl)amino]-6-deoxy-β-cyclodextrin (HEA-β-CD) and per-6-[(2-hydroxyethyl)amino]-6-deoxy-γ-cyclodextrin (HEA-γ-CD), in both solid and liquid phases. A quantitative high-performance liquid chromatography (HPLC) procedure for determining both DHPs in liquid systems was developed. The influence of time, temperature, and molar ratio CB7:DHPs on binding efficiency were systematically examined. Formation of the inclusion complexes was confirmed by thermogravimetric analysis (TGA) and powder X-ray diffraction (XRD) in the solid state and by HPLC in liquid media. It was demonstrated that the solubility of both DHPs in water increases through interaction with CB7. Furthermore, modification of CDs increases their binding affinity to DHP2.