High field NMR techniques and molecular modelling study of the inclusion complexes of the nootropic drug tenilsetam (CAS-997) in cyclodextrins

Abstract

The inclusion complexes of the chiral anti-amnesic drug 3-(2-thienyl)piperazin-2-one (Tenilsetam, CAS-997) with α-, β- and γ-cyclodextrins (CDs) were studied by high resolution ¹H NMR spectroscopy and molecular modelling (MACROMODEL interactive computer program). The partial inclusion of the guest from the secondary hydroxyl side of α-CD was observed in aqueous solution, as well as a deeper insertion into β-CD from the same side; no interactions were evidenced with γ-CD. Diastereoisomeric pairs were observed for both α- and β-CD inclusion complexes. ROESY experiments allowed us to detect the dipolar contacts between protons of the thiophene ring and those of the internal cavity of β-CD. The possible geometry of the complex edifice derived from experimental results was consistent with those obtained by molecular modelling. The formation of hydrogen bonds provides specific interaction sites to differentiate the diastereoisomeric intermolecular inclusion complexes in terms of conformational host–guest adaptation according to available experimental NMR data.