STRUCTURAL AND MOLECULAR MODELING STUDIES OF QUINAZOLINONE ANTICONVULSANTS

Studies of derivatives of the anticonvulsant methaqualone led to the d iscovery that unsaturation in the 2-substituent produced active, but l ess toxic compounds; accordingly, 2-arylethanone derivatives have been developed. The crystal structures of five 2-arylethanone derivatives of methaqualone were determined to probe structure-activity relationsh ips. Although these compounds display different activities, the solid- state and calculated structures are similar: each compound is observed as the enamine tautomer containing an intramolecular hydrogen bond be tween the ethanone and the amine N atom and the molecular conformation s are the same. These studies conclude that recognition of the anticon vulsants arises from specific binding of an ortho substituent on the N (3) phenyl substituent, rather than from binding of a particular confo rmation or tautomeric form adopted by the compound containing an ortho substituent, and that such recognition is characteristic of a broad r ange of anticonvulsant drugs. Crystal data: (1), -oxo-2-(4-pyfidyl)eth yl]3phenyl4(3H)quinazolinone, C2,H15N3O2, M(r) = 341.37, monoclinic, P 2(1), a = 12.1646 (5), b = 5.5988 (2), c = 12.389 (2) angstrom, beta = 90.47 (1)degrees, V = 843.8 (1) angstrom3, Z = 2, D(x) = 1.35 g cm-3, lambda(Cu Kalpha) = 1.5418 angstrom, mu = 7.31 cm-1, T = 293 K, R = 0 .039, 1764 unique reflections; (2), )-2-[2-oxo-2-(4-pyridyl)ethyl-4(3H )-quinazolinone, C21H14ClN3O2, M(r) = 375.82, monoclinic, P2(1)/a, a = 10.9354 (6), b = 14.502 (1), c = 13.019 (1) angstrom, beta = 114.481 (4)degrees, V = 1879.0 (2) angstrom3, Z = 4, D(x) = 1.33 g cm-3, lambd a(Cu Kalpha) = 1.5418 angstrom, mu = 19.87 cm-1, T = 293 K, R = 4.6%, 3550 unique reflections; (3), -2-[2-oxo-2-(4-pyridyl)ethyl]-4(3H)-quin azolinone, C22H17N3O2, M(r) = 355.40, monoclinic, P2(1)/c, a = 5.618 ( 2), b = 30.329 (7), c = 10.456 (4) angstrom, beta = 98.21 (2)degrees, V = 1763.3 (9) angstrom3, Z = 4, D(x) = 1.34 g cm-3, lambda(Mo Kalpha) = 0.71069 angstrom, mu = 0.95 cm-1, T = 293K, R = 5.8%, 3075 unique r eflections; (4), -2-[2-oxo-2-(4-pyridyl)ethyl]-4(3H)-quinazolinone, C2 1H14ClN3O2, M(r) = 375.82, orthorhombic, Pbca, a = 13.9347 (7), b = 9. 6794 (6), c = 25.962 (1) angstrom, V = 3501.7 (3) angstrom3, Z = 8, D( x) = 1.43 g cm-3, lambda(Cu Kalpha) = 1.5418 angstrom, mu = 21.32 cm-1 , T = 293K, R = 6.9%, 3385 unique reflections; (5), ylphenyl)-2-(2-oxo phen-ethyl)-4(3H)-quinazolinone, C23H18N2O2, M(r) = 354.41, orthorhomb ic, Pbca, a = 10.2078( 4), b = 10.237 (1), c = 35.676 (3) angstrom, V = 3728.0 (5) angstrom3, Z = 8, D(x) = 1.26 g cm-3, lambda(Cu Kalpha) = 1.5418 angstrom, mu = 6.62 cm-1, T = 293K, R = 4.8%, 3532 unique refl ections.