¹H NMR and Molecular Modeling Study on the Inclusion Complex β-Cyclodextrin−Indomethacin

The solution structure of the inclusion complex between β-cyclodextrin ( 2 ) and the nonsteroidal anti-inflammatory agent indomethacin sodium salt ( 1 ) [1-( p -chlorobenzoyl)-5-methoxy-2-methylindoleacetic acid sodium salt] is investigated in D 2 O solution via 1 H NMR spectroscopy. The guest molecule 1 exists in solution as a mixture of E and Z isomers in fast exchange on the NMR time scale, as shown by NOE experiments. Low-temperature 1 H NMR spectra on indomethacin methyl ester ( 3 ) (soluble in CH 2 Cl 2 - d 2 ) showed that the Z isomer is the most thermodynamically stable. Geometrical features of the host−guest inclusion complex between 2 and 1 are inferred from intermolecular dipolar contacts obtained by 1D NOE difference spectra and 2D ROESY experiments. A more detailed picture of the solution structure of the complex is obtained by combining NMR structural information and molecular dynamics and energy calculations on the inclusion complexes. Computations took into account the existence of two diastereomeric forms of the guest ( E and Z ), the two possible sites of interaction of the guest molecule with the cavity ( i.e. the p -chlorobenzoyl ring and the indole ring system), and the different topologies for the entry of the guest into the host's cavity. The main finding that can be obtained from both experimental and theoretical data is that the complexation selectively stabilizes the E isomer with respect to Z . The inclusion complex is characterized by the interaction of the p -chlorobenzoyl moiety of 1 E with the lipophilic cavity of the host 2, the entry being through the larger rim of the truncated cone of 2 .