Molecular modeling and crystallographic studies of 4-amino-N-phenylbenzamide anticonvulsants

The molecular structures of five different MES-active N-phenylbenzamides were determined by X-ray diffraction methods, and the conformations of a series of active and inactive benzamides were analyzed by molecular mechanics calculations. The most active compounds adopt a similar, consistent conformation in both the experimentally determined crystallographic structures and in the calculated molecular mechanics structures. This conformation places one o-methyl group proximal to the NH group of the central amide plane and orients the methyl-substituted phenyl ring at an angle of 90 degrees to 120 degrees to the central amide plane. Intermolecular interactions in the crystal structures indicate that hydrogen bonding to the central amide group is the important interaction. The observed consistent conformation facilitates formation of hydrogen bonds to the carbonyl oxygen atom. The conformations of inactive compounds obstruct this interaction. These findings help to outline a model of some of the structural features which this series of benzamides must possess in order to demonstrate MES anticonvulsant activity.