Imidazopyranotacrines as Non-Hepatotoxic, Selective Acetylcholinesterase Inhibitors, and Antioxidant Agents for Alzheimer's Disease Therapy.

Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-yl)ethan-1-one (4) is non-hepatotoxic (cell viability assay on HepG2 cells), a selective but moderately potent EeAChE inhibitor (IC50 = 38.7 ± 1.7 µM), and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 µmol·Trolox/µmol compound).

Crystal structure of ethyl 2-chloro-6-methyl-quinoline-3-carboxyl-ate.

In the title compound, C13H12ClNO2, the dihedral angle between the planes of the quinoline ring system (r.m.s. deviation = 0.029 Å) and the ester group is 54.97 (6)°. The C-O-C-Cm (m = meth-yl) torsion angle is -140.62 (16)°. In the crystal, mol-ecules inter-act via aromatic π-π stacking [shortest centroid-centroid separation = 3.6774 (9) Å] generating (010) sheets.

Crystal structure of 1-methyl-2-[(E)-2-(4-methyl-phen-yl)ethen-yl]-4-nitro-1H-imidazole.

In the title mol-ecule, C13H13N3O2, the planes of the benzene and imidazole rings form a dihedral angle of 7.72 (5)°. In the crystal, mol-ecules are linked by weak C-H⋯N and C-H⋯O hydrogen bonds, forming layers parallel to (100). A weak C-H⋯π inter-action connects these layers into a three-dimensional network. A π-π stacking inter-action, with a centroid-centroid distance of 3.5373 (9) Å, is also observed.

Crystal structure of ethyl 2-chloro-5,8-di-meth-oxy-quinoline-3-carboxyl-ate.

In the title compound, C14H14ClNO4, the dihedral angle between the quinoline ring system (r.m.s. deviation = 0.0142 Å) and ester planes is 18.99 (3)°. The C-O-C-Cm (m = meth-yl) torsion angle is -172.08 (10)°, indicating a trans conformation. In the crystal, the mol-ecules are linked by C-H⋯O and C-H⋯N inter-actions, generating layers lying parallel to (101). Aromatic π-π stacking [centroid-centroid distances = 3.557 (2) and 3.703 (2)Å] links the layers into a three-dimensional network.

Crystal structure of (E)-1-methyl-2-[2-(2-methoxphen-yl)ethen-yl]-4-nitro-1H-imidazole.

In the asymmetric unit of the title compound, C13H13N3O3, the 2-(2-methoxphen-yl)ethenyl unit is connected to the methyl-nitro-imidazole 1-methyl-4-nitro-1H-imidazole moiety. The mol-ecule is quasi-planar and the planes of the two rings form a dihedral angle of 0.92 (11)°. The crystal packing can be described as layers parallel to the (011) plane, stabilized by inter-molecular C-H⋯O hydrogen bonding, resulting in the formation of an infinite three-dimensional network linking these layers. Strong π-π stacking inter-actions are observed, viz. benzene-benzene, imidazole-imidazole and benzene-imidazole rings, with centroid-centroid distances of 3.528 (2), 3.457 (2) and 3.544 (2) Å, respectively. Intensity statistics indicated twinning by non-merohedry, with refined weighs of the twin components of 0.3687:0.6313.

7-Meth-oxy-2-phenyl-quinoline-3-carbaldehyde.

In the title mol-ecule, C17H13NO2, the phenyl ring is inclined to the quinoline ring system by 43.53 (4)°. In the crystal, mol-ecules are linked via C-H⋯O hydrogen bonds, forming double-stranded chains propagating along [011]. These chains are linked via π-π inter-actions involving inversion-related quinoline rings; the shortest centroid-centroid distance is 3.6596 (17) Å.

2-(4-Chloro-phen-yl)-2,3-di-hydro-quinolin-4(1H)-one.

The title mol-ecule, C15H12ClNO, features a di-hydro-quinolin-4(1H)-one moiety attached to a chloro-benzene ring. The heterocyclic ring has a half-chair conformation with the methine C atom lying 0.574 (3) Šabove the plane of the five remaining atoms (r.m.s. deviation = 0.0240 Å). The dihedral angles between the terminal benzene rings is 77.53 (9)°, indicating a significant twist in the mol-ecule. In the crystal, supra-molecular zigzag chains along the c-axis direction are sustained by N-H⋯O hydrogen bonds. These are connected into double chains by C-H⋯π inter-actions.

2-p-Tolyl-2,3-di-hydro-quinolin-4(1H)-one.

In the title mol-ecule, C16H15NO, the tetra-hydro-pyridine ring is in a sofa conformation with the methine C atom forming the flap. The dihedral angle between the benzene rings is 80.85 (8)°. In the crystal, mol-ecules are arranged in alternating double layers parallel to (100) and are connected along [001] by N-H⋯O hydrogen bonds. In addition, weak C-H⋯π inter-actions are observed.

3-Anilino-5,5-di-methyl-cyclo-hex-2-enone.

In the title mol-ecule, C14H17NO, the 5,5-di-methyl-cyclo-hex-2-enone moiety is attached to an aniline group, the dihedral angle subtended [54.43 (3)°] indicating a significant twist. The hexaneone ring has a half-chair conformation with the C atom bearing two methyl groups lying 0.6384 (8) Šabove the plane of the five remaining atoms (r.m.s. deviation = 0.0107 Å). The crystal packing can be described as alternating layers parallel to (-101), which are consolidated by N-H⋯O hydrogen bonds and C-H⋯π inter-actions.

Synthesis, crystal structure and antibacterial activity of new highly functionalized ionic compounds based on the imidazole nucleus.

Several new highly functionalized imidazolium derivatives were synthesized, via appropriate synthetic routes, using imidazole, 1-methylimidazole and 2-phenyl-1-methylimidazole as key intermediates. The antibacterial activity of the prepared compounds was evaluated against: Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella thipymurium using disk-diffusion and MIC methods. Crystal X-ray structures are reported for six compounds.

(2E,2'E)-1,1'-Bis(6-chloro-2-methyl-4-phenyl-quinolin-3-yl)-3,3'-(1,4-phenyl-ene)diprop-2-en-1-one ethyl acetate disolvate.

In the title solvate, C44H30Cl2N2O2·2C4H8O2, the complete polycyclic mol-ecule is generated by inversion symmetry. The dihedral angle between the quinolyl ring system (Q; r.m.s. deviation = 0.020 Å) and the pendant phenyl ring is 78.80 (6)°; the dihedral angle between Q and the central benzene ring is 85.92 (7)°. In the crystal, the components are linked by C-H⋯O and C-H⋯π inter-actions, generating (110) layers. Weak aromatic π-π stacking [centroid-centroid distances = 3.7025 (11) and 3.8124 (10) Å] is also observed.

Methyl 2-(2-methyl-4-nitro-1H-imidazol-1-yl)acetate.

In the crystal of the title compound, C7H9N3O4, mol-ecules are linked by weak C-H⋯O hydrogen bonds into chains along the a-axis direction. The dihedral angle between the ring and the nitro group is 3.03 (6), while that between the ring and the acetate group is 85.01 (3)°.

2-Hy-droxy-methyl-1,3-dimethyl-1H-imidazol-3-ium triiodide.

The crystal packing of the title salt, C6H11N2O(+)·I3 (-), can be described as consisting of alternating layers of cations and anions parallel to the (100) plane along the a-axis direction. The components are linked by O-H⋯I, C-H⋯I and C-H⋯O interactions, generating a three-dimensional network. The O atom deviates from the imidazol ring by 0.896 (2) Å.

2-Hy-droxy-methyl-1,3-dimethyl-1H-benzimidazol-3-ium iodide.

In the cation of the title compound, C10H13N2O(+)·I(-), all non-H atoms, with the exception of the O atom, are essentially coplanar, with a maximum deviation of 0.04 (1) Å. In the crystal, the cations and anions are arranged in layers parallel to (100). The cations are connected to the anions via an O-H⋯I hydrogen bond and there are significant π-π stacking inter-actions between cation layers, with centroid-centroid distances in the range 3.606 (5)-3.630 (5) Å. A weak intra-molecular C-H⋯O hydrogen bond is also observed. The crystal studied was an inversion twin with refined components of 0.52 (5) and 0.48 (5).

3-(1H-1,3-Benzimidazol-2-yl)-2,7-dimeth-oxy-quinoline.

In the title mol-ecule, C(18)H(15)N(3)O(2), the dihedral angle between the quinoline and benzimidazole ring systems is 23.57 (5)°. The C atoms of the meth-oxy groups are both close to being coplanar with their attached ring systems [deviations = 0.193 (2) and -0.020 (2) Å]. An intra-molecular N-H⋯O hydrogen bond closes an S(6) ring. In the crystal, N-H⋯N hydrogen bonds link the mol-ecules into C(4) chains propagating in [010]. Weak C-H⋯π inter-actions also occur.

4,5-Dibromo-1,2-dimethyl-1H-imidazol-3-ium bromide.

In the title salt, C(5)H(7)Br(2)N(2) (+)·Br(-), the cation and anion are connected by an N-H⋯Br hydrogen bond. In the crystal, there are inter-calated layers parallel to (10-2) in which bromide ions are located between the cations. Weak inter-molecular C-H⋯Br hydrogen bonds are also observed.

2-Chloro-3-[(E)-(hydrazin-1-yl-idene)meth-yl]-6-meth-oxy-quinoline.

In the title compound, C(11)H(10)ClN(3)O, the quinoline ring system is essentially planar, the r.m.s. deviation for the non-H atoms being 0.014 (2) Šwith a maximum deviation from the mean plane of 0.0206 (14) Šfor the C atom bonded to the -CH-N=NH(2) group. In the crystal, molecules are linked via N-H⋯O and N-H⋯N hydrogen bonds, forming zigzag layers parallel to (010).

rac-2-(2-Chloro-6-methyl-quinolin-3-yl)-2,3-dihydro-quinolin-4(1H)-one.

In the title compound, C(19)H(15)ClN(2)O, the quinoline ring forms a dihedral angle of 43.24 (1)° with the benzene ring of the dihydroquinolinyl system. In the crystal, mol-ecules are linked through a single weak C-H⋯O hydrogen bond, forming ribbons which extend along (100), giving alternating zigzag mol-ecular layers which stack down the b-axis direction.

Ethyl 3-(2-chloro-5,8-dimeth-oxy-quinolin-3-yl)-2-cyano-oxirane-2-carboxyl-ate.

The title mol-ecule, C(17)H(15)ClN(2)O(5), contains a quinolyl unit linked to a functionalized oxirane system with a 2,3-trans arrangement of the substituents (ester group versus quinol-yl). The structure can be described as being built up from zigzag layers parallel to (1[Formula: see text]0). The heterocyclic ring of the quinolyl unit forms a dihedral angle of 60.05 (1)° with the oxirane plane. The crystal packing is stabilized by inter-molecular C-H⋯O and C-H⋯N hydrogen bonding, resulting in the formation of an infinite three-dimensional network and reinforcing the cohesion between the layers.

2-Hy-droxy-methyl-1,3-dimethyl-imidazolium iodide.

The crystal packing of the title compound, C(6)H(11)N(2)O(+)·I(-), can be described as inter-calated layers lying parallel to (010), with the iodide ions located between the cations. A weak intra-molecular C-H⋯O hydrogen bond occurs within the cation. In the crystal, inter-molecular O-H⋯I hydrogen bonds result in the formation of a three-dimensional network and reinforce the cohesion of the ionic structure.