Conformational analysis of the antiinflammatory fenamates: a molecular mechanics and semiempirical molecular orbital study

Abstract The molecular structure and conformational properties of structurally related fenamates have been calculated by the molecular mechanics method and both AM1 and PM3 molecular orbital methods, and the results have been compared with crystal structure data. For the meclofenamic, mefenamic and flufenamic acids the two molecular orbital methods give values of the bridge torsion angles C2-C1-N1-C8 and C1-N1-C8-C9 in closest agreement with the crystal structure, and the molecular mechanics method yields values within about 20 ° of that found in the crystal structures. For niflumic acid the PM3 molecular orbital reproduced the X-ray crystallographic values. Meclofenamic acid is the only fenamate that adopts an almost perpendicular arrangement between the aromatic rings. This conformation causes difficulties for the conjugation of the amino group and the two aromatic rings simultaneously, localizing the HOMO in the phenyl ring bearing the carboxyl group and the nitrogen atom of the amino group. Global superimposition, based on the fitting of the common negative regions of the electrostatic potential, for all fenamates, yields good overlapping except an additional region of interaction around the bridging amino group and the second phenyl ring moiety for meclofenamic acid.