MOLECULAR MODELING AND CRYSTALLOGRAPHIC STUDIES OF 4-AMINO-N-PHENYLBENZAMIDE ANTICONVULSANTS

被引:14
作者
DUKE, NEC
CODDING, PW
机构
[1] UNIV CALGARY,DEPT CHEM,CALGARY T2N 1N4,ALBERTA,CANADA
[2] UNIV CALGARY,DEPT PHARMACOL & THERAPEUT,CALGARY T2N 1N4,ALBERTA,CANADA
关键词
D O I
10.1021/jm00088a016
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 omicron-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.
引用
收藏
页码:1806 / 1812
页数:7
相关论文
共 20 条
[1]  
ALLINGER NL, 1982, MMP2 MOL MECHANICS
[2]  
BEURSKENS PT, 1982, DIRDIF DIRECT METHOD
[3]   ANTICONVULSANT ACTIVITY OF SOME 4-AMINOPHENYLACETAMIDES [J].
CLARK, CR ;
DAVENPORT, TW .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1987, 76 (01) :18-20
[4]   SYNTHESIS AND ANTICONVULSANT ACTIVITY OF ANALOGS OF 4-AMINO-N-(1-PHENYLETHYL)BENZAMIDE [J].
CLARK, CR ;
DAVENPORT, TW .
JOURNAL OF MEDICINAL CHEMISTRY, 1987, 30 (07) :1214-1218
[5]   ANTICONVULSANT ACTIVITY OF 2-AMINOBENZANILIDES AND 3-AMINOBENZANILIDES [J].
CLARK, CR ;
LIN, CM ;
SANSOM, RT .
JOURNAL OF MEDICINAL CHEMISTRY, 1986, 29 (08) :1534-1537
[6]   ANTICONVULSANT ACTIVITY OF SOME 4-AMINOBENZANILIDES [J].
CLARK, CR ;
SANSOM, RT ;
LIN, CM ;
NORRIS, GN .
JOURNAL OF MEDICINAL CHEMISTRY, 1985, 28 (09) :1259-1262
[7]   ANTICONVULSANT ACTIVITY OF SOME 4-AMINOBENZAMIDES [J].
CLARK, CR ;
WELLS, MJM ;
SANSOM, RT ;
NORRIS, GN ;
DOCKENS, RC ;
RAVIS, WR .
JOURNAL OF MEDICINAL CHEMISTRY, 1984, 27 (06) :779-782
[8]  
CODDING PW, 1985, MOL PHARMACOL, V28, P178
[9]   X-RAY SCATTERING FACTORS COMPUTED FROM NUMERICAL HARTREE-FOCK WAVE FUNCTIONS [J].
CROMER, DT ;
MANN, JB .
ACTA CRYSTALLOGRAPHICA SECTION A-CRYSTAL PHYSICS DIFFRACTION THEORETICAL AND GENERAL CRYSTALLOGRAPHY, 1968, A 24 :321-&
[10]   APPLICATION OF PHASE RELATIONSHIPS TO COMPLEX STRUCTURES .3. OPTIMUM USE OF PHASE RELATIONSHIPS [J].
GERMAIN, G ;
MAIN, P ;
WOOLFSON, MM .
ACTA CRYSTALLOGRAPHICA SECTION A-CRYSTAL PHYSICS DIFFRACTION THEORETICAL AND GENERAL CRYSTALLOGRAPHY, 1971, A 27 (JUL1) :368-&