HIGH-FIELD NMR TECHNIQUES AND MOLECULAR MODELING STUDY OF THE INCLUSION COMPLEXES OF THE NOOTROPIC DRUG TENILSETAM (CAS-997) IN CYCLODEXTRINS

The inclusion complexes of the chiral anti-amnesic drug 3-(2-thienyl)piperazin-2-one (Tenilsetam, CAS-997) with alpha-, beta- and gamma-cyclodextrins (CDs) were studied by high resolution H-1 NMR spectroscopy and molecular modelling (MACROMODEL interactive computer program). The partial inclusion of the guest from the secondary hydroxyl side of alpha-CD was observed in aqueous solution, as well as a deeper insertion into beta-CD from the same side; no interactions were evidenced with gamma-CD. Diastereoisomeric pairs were observed for both alpha- and beta-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 beta-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.