Synthesis, In Silico, and In Vitro Evaluation of Anti-Leishmanial Activity of Oxadiazoles and Indolizine Containing Compounds Flagged against Anti-Targets.

Due to the lack of approved vaccines against human leishmaniasis and the limitations of the current chemotherapy inducing side effects and drug resistance, development of new, effective chemotherapeutic agents is essential. This study describes the synthesis of a series of novel oxadiazoles and indolizine-containing compounds. The compounds were screened in silico using an EIIP/AQVN filter followed by ligand-based virtual screening and molecular docking to parasite arginase. Top hits were further screened versus human arginase and finally against an anti-target battery to tag their possible interactions with proteins essential for the metabolism and clearance of many substances. Eight candidate compounds were selected for further experimental testing. The results show measurable in vitro anti-leishmanial activity for three compounds. One compound with an IC50 value of 2.18 µM on Leishmania donovani intramacrophage amastigotes is clearly better positioned than the others as an interesting molecular template for further development of new anti-leishmanial agents.

Synthesis, X-ray structure, in silico calculation, and carbonic anhydrase inhibitory properties of benzylimidazole metal complexes.

Three coordination compounds of formula {M(bmim)2Cl2} were synthetised (M = Co, Zn, and Hg) and fully characterised. Each complex incorporates 1-benzyl-2-methylimidazole (bmim) as ligand. The coordination polyhedron around the metal center for all complexes has a quasi-regular tetragonal geometry. Density functional theory calculations were carried out on the title compounds and as well on hypothetical complexes (Cu, Ni), in order to elucidate their electronic and molecular structure. The calculations reproduced the Co, Zn, and Hg experimental structures and could predict stable complexes in the case of Ni(II) and Cu(II) ions. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the three complexes were investigated. Only compound {Hg(bmim)2Cl2} (3) exhibited a modest inhibitory effect against hCA I, probably due to the affinity of Hg(II) for His residues at the entrance of the active site cavity.

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.

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).

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.

2-(2-Chloro-6,7-dimethyl-quinolin-3-yl)-2,3-dihydro-quinolin-4(1H)-one.

In the title mol-ecule, C(20)H(17)ClN(2)O, the dihedral angle between the mean plane of the quinoline ring system and the benzene ring of the dihydro-quinolinone moiety is 57.84 (8)°. In the crystal, mol-ecules are linked into centrosymmetric dimers via pairs of inter-molecular N-H⋯N hydrogen bonds. These dimers are further stabilized by weak π-π stacking inter-actions between pyridine rings with a centroid-centroid distance of 3.9414 (12) Å.

2-Chloro-quinoline-3-carboxylic acid.

The crystal structure of the title compound, C(10)H(6)ClNO(2), can be described by two types of crossed layers which are parallel to (110) and (10). The crystal packing is stabilized by inter-molecular C-H⋯O and O-H⋯N hydrogen bonds, resulting in the formation of a two-dimensional network and reinforcing the cohesion of the structure.