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.

Potent anticholinesterasic and neuroprotective pyranotacrines as inhibitors of beta-amyloid aggregation, oxidative stress and tau-phosphorylation for Alzheimer's disease.

Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized 2-chloroquinolin-3-yl substituted PyranoTacrines (PTs) as multipotent tacrine analogues for Alzheimer's disease (AD) therapy. Among these compounds, 1-(5-amino-4-(2-chloro-7-methoxyquinolin-3-yl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrano [2,3-b]quinolin-3-yl)éthanone (9) and ethyl 5-amino-4-(2-chloroquinolin-3-yl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinoline-3-carboxylate (4) were found to be non-neurotoxic agents in human neuroblastoma SHSY5Y cells. Compounds 9 (IC50 = 0.47 ± 0.13 µM) and 4 (IC50 = 0.48 ± 0.05 µM) are potent, mixed-type (9: Ki = 0.0142 ± 0.003 µM), and selective EeAChE inhibitors, binding at the both catalytic and peripheral anionic site of the enzyme. Compounds 9 and 4 are neuroprotective agents at low µM concentrations upon decreased viability of SHSY5Y cells induced by oxidative stress, and stimulators of GSK3ß-dependent tau phosphorylation. In addition, molecules 9 and 4 effectively counteract Aß-aggregation on exposure to Aß1-40, as well as Aß1-40 aggregation-dependent tau-oligomerization and phosphorylation in (396)Ser, which could be ascribed to the anti-aggregating properties shown in vitro. Thus, a new family of tacrine analogues, whose potent AChEI activity is linked to both their Aß-aggregating and tau-phosphorylation inhibitory capacities, has been discovered for the potential treatment of AD.

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 13-(2-meth-oxy-phenyl)-3,4-di-hydro-2H-indazolo[1,2-b]phthalazine-1,6,11(13H)-trione.

In the title compound, C22H18N2O4, the three fused rings of the pyrazolo-phthalazine moiety are coplanar (r.m.s. deviation = 0.027 Å). The cyclo-hexene ring fused to the pyrazolidine ring, so forming the indazolophthalazine unit, has a half-chair conformation. The benzene ring is almost normal to the mean plane of the pyrazolo-phthalazine moiety, with a dihedral angle of 87.21 (6)° between their planes. In the crystal, mol-ecules are linked by pairs of C-H⋯O hydrogen bonds forming inversion dimers. The dimers are linked via C-H⋯π inter-actions, forming slabs parallel to (100). Between the slabs there are weak π-π inter-actions [shortest inter-centroid distance = 3.6664 (9) Å], leading to the formation of a three-dimensional structure.

Crystal structure of 1-[(1-methyl-5-nitro-1H-imidazol-2-yl)meth-yl]pyridinium iodide.

In the title salt, C10H11N4O2 (+)·I(-), the asymmetric unit consists of a pyridinium cation bearning a (1-methyl-5-nitro-1H-imidazol-2-yl)methyl group at the N position and an iodide anion. The imidazole ring is quasiplanar, with a maxiumum deviation of 0.0032 (16) Å, and forms a dihedral angle of 67.39 (6)° with the plane of the pyridinium ring. The crystal packing can be described as alternating zigzag layers of cations parallel to the (001) plane, which are sandwiched by the iodide ions. The structure features two types of hydrogen bonds (C-H⋯O and C-H⋯I), viz. cation-anion and cation-cation, which lead to the form ation of a three-dimensional network.

Crystal structure of (2S/2R,3S/3R)-3-hydroxy-2-phenyl-chroman-4-one.

In the title mol-ecule, C15H12O3, the C atoms bearing the hy-droxy group and the phenyl ring are disordered over two sets of sites with refined occupancies of 0.573 (7) and 0.427 (7). There is also disorder of the phenyl ring but the hy-droxy group was refined as ordered. The dihedral angles between the benzene ring of the chromane ring system and the phenyl ring are 89.7 (2)° for the major component of disorder and 72.1 (3)° for the minor component. Both disorder components of the the di-hydro-pyran ring are in a half-chair conformation. In the crystal, mol-ecules are linked by pairs of O-H⋯O hydrogen bonds, forming inversion dimers with an R 2 (2)(10) graph-set motif. Weak C-H⋯π inter-actions link these dimers into ladders along [001].

Crystal structure of {bis-[(1H-benzimid-azol-2-yl-κN (3))meth-yl]sulfane}dichloridomercury(II).

In the asymmetric unit of the title compound, [HgCl2(C16H14N4S)], the Hg(II) cation is linked to two Cl atoms and two imidazole N atoms of the chelating bis-[(1H-benzimidazol-2-yl)meth-yl]sulfane ligand, forming a slightly distorted tetra-hedral environment. The substitued imidazole rings of the ligand are almost perfectly planar [with maximum deviations of 0.017 (3) and 0.012 (3) Å] and form a dihedral angle of 42.51 (5)°. The crystal packing can be described as alternating layers parallel to (010). In this arrangement, N-H⋯Cl hydrogen bonds between the N-H groups of the benzimidazole moieties and chloride ligands are responsible for the formation of the chain-like packing pattern along [010] exhibiting a C(6) graph-set motif.

Crystal structure of catena-poly[1,3-di-benzyl-benzimidazolium [[chlorido-mercurate(II)]-di-µ-chlorido]].

The asymmetric unit of the polymeric title compound, {(C21H19N2)[HgCl3]} n , comprises one-half of the cationic mol-ecule, the other half being generated by application of twofold rotation symmetry, one Hg and two Cl atoms. The Hg(II) atom, lying on a twofold rotation axis, exhibits a distorted triangular coordination environment and is surrounded by three Cl atoms with Hg-Cl distances in the range 2.359 (2)-2.4754 (13) Å. Two additional longer distances [Hg⋯Cl = 3.104 (14) Å] lead to the formation of polymeric [HgCl1/1Cl4/2](-) chains extending along [001]. The crystal packing can be described by cationic layers alternating parallel to (-110) with the anionic chains located between the layers. The packing is consolidated by π-π stacking inter-actions between the benzene rings of the central benzimidazole entities, with centroid-to-centroid distances of 3.643 (3) Å.

Crystal structure of 13-phenyl-2,3,4,13-tetra-hydro-1H-indazolo[1,2-b]phthalazine-1,6,11-trione.

The title compound, C21H16N2O3, consists of an indazolone moiety, bearing a phenyl group, fused to a phthalazine ring system (r.m.s. deviation = 0.018 Å). The phenyl ring is almost normal to the mean plane of the five-membered ring of the indazolone moiety, making a dihedral angle of 89.64 (7)°. The six-membered ring of the indazolone moiety has an envelope conformation, with the central methyl-ene C atom as the flap. In the crystal, mol-ecules are linked via C-H⋯O hydrogen bonds, forming slabs parallel to the bc plane. The slabs are linked via C-H⋯π and π-π inter-actions [the shortest inter-centroid distance involving rings of pyrazolo-phthalazine moieties is 3.6430 (8) Å], forming a three-dimensional structure.

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.

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.

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)°.