STRUCTURAL AND MOLECULAR MODELING STUDIES OF QUINAZOLINONE ANTICONVULSANTS

Studies of derivatives of the anticonvulsant methaqualone led to the discovery that unsaturation in the 2-substituent produced active, but less 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 relationships. 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 between the ethanone and the amine N atom and the molecular conformations are the same. These studies conclude that recognition of the anticonvulsants arises from specific binding of an ortho substituent on the N(3) phenyl substituent, rather than from binding of a particular conformation or tautomeric form adopted by the compound containing an ortho substituent, and that such recognition is characteristic of a broad range of anticonvulsant drugs. Crystal data: (1), 2-[2-oxo-2-(4-pyfidyl)ethyl]3phenyl4(3H)quinazolinone, C2,H15N3O2, M(r) = 341.37, monoclinic, P2(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), 3-(2-chlorophenyl)-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, lambda(Cu Kalpha) = 1.5418 angstrom, mu = 19.87 cm-1, T = 293 K, R = 4.6%, 3550 unique reflections; (3), 3-(2-methylphenyl)-2-[2-oxo-2-(4-pyridyl)ethyl]-4(3H)-quinazolinone, 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 reflections; (4), 3-(4-chlorophenyl)-2-[2-oxo-2-(4-pyridyl)ethyl]-4(3H)-quinazolinone, C21H14ClN3O2, 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), 3-(2-methylphenyl)-2-(2-oxophen-ethyl)-4(3H)-quinazolinone, C23H18N2O2, M(r) = 354.41, orthorhombic, 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 reflections.