Cyheptamide and 3-hydroxy-3-phenacyloxindole structural similarity to diphenylhydantoin as the basis for anticonvulsant activity

Abstract

The molecular structures of cyheptamide and 3-hydroxy-3- phenacyloxindole were determined by X-ray diffraction methods. The amide group in both compounds exhibits delocalization of the pi-electrons over the three atoms (N, C, and O), while the bond linking the amide to the tetrahedral carbon atom is a single bond. These structural features are also present in two drugs used for the treatment of generalized tonic-clonic ( GTC ) seizures, namely, carbamazepine and diphenylhydantoin. The shapes of cyheptamide , 3-hydroxy-3- phenacyloxindole , and carbamazepine have three features that are the same and can be simultaneously overlapped, the amide and two hydrophobic regions, whereas diphenylhydantoin fits two of the three regions at one time. These structural and electronic features are analyzed in light of current models for anticonvulsant activity.

Structure of ranitidine hydrochloride

“…The angles between plane normals of the six-and fivemembered rings are 3.4 (4) for A, 0.8 (4) for B and 4.3 (3) ° for C. The corresponding bond lengths and angles for the three independent molecules are similar. The molecular parameters for the six-and five-membered rings agree well with those of other structures (Codding, Lee & Richardson, 1984;Vega, Jimenez-Garay, Lopez-Castro & Marquez, 1980).…”

Structure of 3,3-dimethoxyindolin-2-one

“…However, the geometry at the N atom is planar and the lengthening of the carbonyl double bond to 1.226 (4)A and the shortening of the N(1)---C(8) distance to 1-412 A are consistent with electron delocalization over the --NH---CO moiety. Similar geometries have also been observed in other structures (James & Williams, 1972;Codding, Lee & Richardson, 1984;De, 1990;De & Kusunoki, 1991). The C(2)---C(3) separation (Itai, Iitaka & Yubo, 1978;Chakraborty & Talapatra, 1985;De, 1990).…”

Structural and molecular modeling studies of quinazolinone anticonvulsants

“…Features that are more specific to anticonvulsants are becoming evident with increased development and study of active compounds. Early work identified the importance of hydrophobic groups and electron-donating regions (Camerman & Camerman, 1980) and a mutually perpendicular orientation of a single hydrophobic group and the electron pair (Codding, Lee & Richardson, 1984). Recently, systematic investigation of sets of similar compounds, including phenylpiperidinopyridazines (Codding, Duke, Aha, Palmer, McClurg & Szkaradzinska, 1990), 4-amino-Nphenylbenzamides (Duke & Codding, 1992), benzodiazepines (Hamor & Martin, 1983;Popp, 1977;Sternbach, Sancilio & Blount, 1974) and the quinazolinone compounds reported herein, emphasize four common features: (i) that the molecular conformations of active and inactive compounds are similar, yet (ii) the presence of ortho substituents on a phenyl ring results in an increase in activity, (iii) a para substituent on the same ring results in a decrease in activity, and (iv) the chemical properties of the group in the ortho position are not directly related to the activity of the compound.…”