NMR CONFORMATIONAL STUDIES OF FENAMATE NONSTEROIDAL ANTIINFLAMMATORY DRUGS

H-1 and C-13 NMR spectra of the non-steroidal anti-inflammatory drugs mefenamic acid, meclofenamic acid and flufenamic acid were assigned and the solution dynamics and conformations of the compounds were probed by the analysis of NMR chemical shifts, temperature coefficients, (3)J(C,H) coupled constants, nuclear Overhauser enhancement (NOE) effects and saturation transfer experiments. At low concentrations the anthranilic acid derivatives (the fenamates) exist as monomer units with intramolecular hydrogen bonding between the amine proton and the carboxylic acid group. At concentrations of 10 mM and above, solution aggregates exist. The intermolecular association does not disrupt the intramolecular N-H...O=C hydrogen bonding, resulting in a similar conformation for mefenamic and flufenamic acids at both low sind high concentrations. Meclofenamic acid has an additional intramolecular hydrogen bond, resulting in a slightly different conformation to the other two fenamates. The results from this conformational study are of potential value in molecular and pharmacophore modelling studies on the bioactive conformations of these drugs.