Crystal structure and conformation of linomide [N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1 -methyl-2-oxo-quinoline-3-carboxamide]: A novel immunomodulator

Abstract

Linomide [N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide] is a new immunomodulator from Phamacia Laboratories, Helsingborg, Sweden. Linomide (LS-2616) has delayed hypersensitivity in rat skin, potentiates mouse natural killer cell activity, and stimulates polyclonal T-cell activation. It has been shown that LS-2616 abolishes the effects of continuous cyclosporine treatment in experimental models. Crystal structure of LS-2616 has been undertaken as a first step in the establishment of a possible structure–function relationship for the drug. Crystals of LS-2616 (C18H16N2O3) obtained from methylene chloride are monoclinic, of space group P21/a with the following crystallographic parameters: a = 8.793(1) A, b = 22.349(3) A, c = 7.808(1) A, β = 92.96(1)°, V = 1532.3(6) A3, ρobs = 1.34 Mg/m3, ρcalc = 1.337 Mg/m3, and Z = 4. The structure was solved with CAD-4 data using MULTAN programs and refined to a final R value of 0.041. The N-methyl carboxamide is in the cis configuration and is turned away from the quinoline ring by 87°. FK506 is a novel 23-membered macrolide lactone which is currently used for bone marrow and organ transplantations. The crystal structure of FK506 has been published. The absolute configuration of FK506 was established as a cis-amide which contains a L-pipecolic acid moiety. Preliminary modeling studies of FK506 with LS-2616 revealed that this cis conformation for the N-methyl carboxamide leads to a lower binding energy than the corresponding trans conformation. The plane of the phenyl group is inclined by 95° to the carboxamide plane. The molecule has the familiar herring-bone type of packing, characteristic of the polyphenyl molecules, stabilized by O–H ⋅ ⋅ ⋅ O and C–H ⋅ ⋅ ⋅ O hydrogen bonds involving the hydroxyl group and the ketone substituents on the quinoline ring and the N-methyl group of the carboxamide.