Synthesis, biological evaluation, theoretical calculations, QSAR and molecular docking studies of novel arylaminonaphthols as potent antioxidants and BChE inhibitors.

A completely green protocol was developed for the synthesis of a series of arylaminonaphthol derivatives in the presence of N-ethylethanolamine (NEEA) as a catalyst under ultrasonic irradiation and solventless conditions. The major assets of this methodology were the use of non-toxic organic medium, available catalyst, mild reaction condition, and good to excellent yield of desired products. All of the synthesized products were screened for their in vitro antioxidant activity using DPPH, ABTS, and Ferric-phenanthroline assays and it was found that most of them are potent antioxidant agents. Also, their butyrylcholinesterase inhibitory activity has been investigated in vitro. All tested compounds exhibited potential inhibitory activity toward BuChE when compared to standard reference drug galantamine, however, compounds 4r, 4u, 4 g and 4x gave higher butyrylcholinesterase inhibitory with IC50 values of 14.78 ± 0.65 µM, 16.18 ± 0.50 µM, 20.00 ± 0.50 µM, and 20.28 ± 0.08 µM respectively. On the other hand, we employed density functional theory (DFT), calculations to analyze molecular geometry and global reactivity descriptors, and MESP analysis to predict electrophilic and nucleophilic attacks. A quantitative structure-activity relationship (QSAR) investigation was conducted on the antioxidant and butyrylcholinesterase properties of 25 arylaminonaphthol derivatives, resulting in robust and satisfactory models. To evaluate their anti-Alzheimer's activity, compounds 4 g, 4q, 4r, 4u, and 4x underwent docking simulations at the active site of the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing why these compounds displayed superior activity, consistent with the biological findings.

Ene reactions of 2-borylated α-methylstyrenes: a practical route to 4-methylenechromanes and derivatives.

4-Methylenechromanes were prepared via a three-step process from 2-borylated α-methylstyrenes. This sequence is based on a key glyoxylate-ene reaction catalyzed by scandium(iii) triflate. The resulting γ-hydroxy boronates, which cyclise to seven-membered homologues of benzoxaborole on silica gel, were cleanly oxidized with sodium perborate, and then cyclised under Mitsunobu conditions. Additionally, several further functional transformations of 4-methylenechromanes or their precursors were carried out to illustrate the synthetic potential of these intermediates.

Synthesis, molecular docking studies, and biological evaluation of novel alkyl bis(4-amino-5-cyanopyrimidine) derivatives.

A series of bis(4-amino-5-cyano-pyrimidines) was synthesized and evaluated as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To further explore the multifunctional properties of the new derivatives, their antioxidant and antibacterial activities were also tested. The results showed that most of these compounds could effectively inhibit AChE and BChE. Particularly, compound 7c exhibited the best AChE inhibitory activity (IC50 = 5.72 ± 1.53 µM), whereas compound 7h was identified as the most potent BChE inhibitor (IC50 = 12.19 ± 0.57 µM). Molecular modeling study revealed that compounds 7c, 7f, and 7b showed a higher inhibitory activity than that of galantamine against both AChE and BChE. Anticholinesterase activity of compounds 7h, 7b, and 7c was significant in vitro and in silico for both enzymes, since these compounds have hydrophobic rings (Br-phenyl, dimethyl, and methoxyphenyl), which bind very well in both sites. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activities. Indeed, in the superoxide-dimethyl sulfoxide alkaline assay, compound 7j showed very high inhibition (IC50 = 0.37 ± 0.28 µM). Also, compound 7l exhibited strong and good antibacterial activity against Staphylococcus epidermidis and Staphylococcus aureus, respectively. Taking into account the results of biological evaluation, further modifications will be designed to increase potency on different targets. In this study, the obtained results can be a new starting point for further development of multifunctional agents for the treatment of Alzheimer's disease.

A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.

In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.

4-(2-Nitro-benz-yl)-3-phenyl-3,4-di-hydro-2H-1,4-benzoxazin-2-ol.

The title compound, C21H18N2O4, crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. In both mol-ecules the oxazine ring has an envelope conformation with the hydroxyl-substituted C atom as the flap. The nitro-benzyl ring and the phenyl ring are almost normal to the mean plane of the benzooxazine ring system with dihdral angles of 85.72 (15) and 82.69 (15)°, respectively, in mol-ecule A, and 85.79 (15) and 87.72 (15)°, respectively, in mol-ecule B. The main difference in the conformation of the two mol-ecules concerns the dihedral angle between the nitro-benzyl ring and the phenyl ring, viz. 79.67 (18) in mol-ecule A and 71.13 (18)° in mol-ecule B. In the crystal, the A and B mol-ecules are linked by an O-H⋯O hydrogen bond. These units are then linked via C-H⋯O hydrogen bonds, forming sheets lying parallel to (010). Further C-H⋯O hydrogen bonds link the sheets to form a three-dimensional network. There are also O-H⋯π and C-H⋯π inter-actions present, reinforcing the three-dimensional structure.

2-(4-Chloro-phen-yl)-4-phenyl-1,2-di-hydro-quinazoline.

In the title compound, C20H15ClN2, the pyrimidine ring is in a flattened half-chair conformation. The phenyl and chloro-substituted benzene rings form dihedral angles of 84.97 (5) and 80.23 (4)°, respectively, with the benzene ring of the di-hydro-quinazoline group. The dihedral angle between the phenyl and chloro-substituted benzene rings is 61.71 (5)°. In the crystal, mol-ecules are arranged in inter-secting layers parallel to (101) and (-102), with N-H⋯N hydrogen bonds linking mol-ecules along [010]. In addition, a weak C-H⋯π inter-action is observed.

2-(2-Chloro-8-methyl-quinolin-3-yl)-4-phenyl-1,2-di-hydro-quinazoline.

In the title compound, C24H18ClN3, the di-hydro-quinazoline and methyl-substituted quinoline benzene rings make a dihedral angle of 78.18 (4)° and form dihedral angles of 45.91 (5) and 79.80 (4)°, respectively, with the phenyl ring. The dihedral angle between the phenyl ring of di-hydro-quinazoline and the methyl-substituted benzene ring of quinoline is 78.18 (4)°. The crystal packing can be described as crossed layers parallel to the (011) and (0-11) planes. The structure features N-H⋯N hydrogen bonds and π-π inter-actions [centroid-centroid distance between phenyl rings = 3.7301 (9) Å].

Erratum: Crystal structure and Hirshfeld surface analysis of N-[(2-hy-droxy-naphthalen-1-yl)(3-methyl-phen-yl)meth-yl]acetamide. Corrigendum.

[This corrects the article DOI: 10.1107/S2056989018008423.].

Erratum: Crystal structure and Hirshfeld surface analysis of (Z)-4-(4-hy-droxy-benzyl-idene)-3-methyl-isoxazol-5(4H)-one. Corrigendum.

[This corrects the article DOI: 10.1107/S2056989018007867.].

2-Hy-droxy-N-(4-meth-oxy-benz-yl)-4-nitro-anilinium chloride.

The crystal structure of the title compound, C(14)H(15)N(2)O(4) (+)·Cl(-), can be described as being composed of layers containing both cations and anions that are staggered along [010]. Two types of the hydrogen bonds are observed, viz. cation-anion and cation-cation. The chloride anions are acceptors of the strong hydrogen bonds donated by the secondary amine and the hy-droxy groups. The packing is also stabilized by weak C-H⋯O inter-molecular hydrogen bonds. An intra-molecular N-H⋯O inter-action also occurs.

Structural study and Hirshfeld surface analysis of (Z)-4-(2-meth-oxy-benzyl-idene)-3-phenyl-isoxazol-5(4H)-one.

The title compound, C17H13NO3, adopts a Z configuration about the C=C bond. The isoxazole and meth-oxy-benzyl-idene rings are almost coplanar with a dihedral angle of 9.63 (7)° between them. In contrast, the phenyl substituent is twisted significantly out of the plane of the oxazole ring, with the two rings inclined to each other by 46.22 (4)°. The crystal structure features C-H⋯O, C-H⋯N and C-H⋯π hydrogen bonds and π-π contacts. An analysis of the Hirshfeld surfaces points to the importance of H⋯H, H⋯C/C⋯H and H⋯O/O⋯H contacts. The included surface areas of the title compound were compared to those of the isomeric structure (Z)-4-(4-meth-oxy-benzyl-idene)-3-phenyl-isoxazol-5(4H)-one [Zhang et al. (2015 ▸). CrystEngComm, 17, 7316-7322].

Crystal structure and Hirshfeld surface analysis of (Z)-3-methyl-4-(thio-phen-2-yl-methyl-idene)isoxazol-5(4H)-one.

The title compound, C9H7NO2S crystallizes with two independent mol-ecules (A and B) in the asymmetric unit with Z = 8. Both mol-ecules are almost planar with a dihedral angle between the isoxazole and thio-phen rings of 3.67 (2)° in mol-ecule A and 10.00 (1) ° in mol-ecule B. The packing of mol-ecules A and B is of an ABAB⋯ type along the b-axis direction, the configuration about the C=C bond is Z. In the crystal, the presence of C-H⋯O, C-H⋯ N and π-π inter-actions [centroid-centroid distances of 3.701 (2) and 3.766 (2) Å] link the mol-ecules into a three-dimensional architecture. An analysis of Hirshfeld surfaces shows the importance of C-H⋯O and C-H⋯N hydrogen bonds in the packing mechanism of the crystalline structure.

N-[(2-Chloro-8-methyl-quinolin-3-yl)meth-yl]-4-meth-oxy-aniline.

In the title compound, C(18)H(17)ClN(2)O, the quinoline ring system is essentially planar; the r.m.s. deviation for the non-H atoms is 0.04 Šwith a maximum deviation from the mean plane of 0.026 (4) Šfor the C atom bonded to the -CH(2)- group. The meth-oxy-substituted benzene ring forms a dihedral angle of 70.22 (4)° with this ring system. The crystal structure can be described as zigzag layers in which the quinoline ring systems are parallel to (011) and molecules are connected via inter-molecular N-H⋯N hydrogen bonds, forming chains along [100]. The crystal studied was an inversion twin with a 0.86 (5):0.14 (5) domain ratio.

Diethyl 2,6-dimethyl-pyridine-3,5-dicarboxyl-ate at 100†K.

In the structure of the title compound, C(13)H(17)NO(4), the packing is stabilized by weak C-H⋯O and C-H⋯π inter-actions, resulting in the formation of a three-dimensional network.

Ethyl 4-(2-chloro-quinolin-3-yl)-1-phenyl-1H-pyrrole-3-carboxyl-ate.

In the mol-ecule of the title compound, C(22)H(17)ClN(2)O(2), the dihedral angles formed by the pyrrole ring with the quinoline and phenyl rings are 67.93 (8) and 28.40 (11)°, respectively. In the crystal structure, mol-ecules are linked into dimers by inter-molecular C-H⋯O hydrogen bonds.

Crystal structure and Hirshfeld surface analysis of (Z)-4-(4-hy-droxy-benzyl-idene)-3-methyl-isoxazol-5(4H)-one.

The title compound, C11H9NO3, contains an isoxazole and a hy-droxy-benzyl-idene ring, which are inclined to each another by 3.18 (8)°. There is an intra-molecular C-H⋯O contact forming an S(7) ring. In the crystal, mol-ecules stack head-to-tail in columns along the b-axis direction, linked by offset π-π inter-actions [inter-centroid distances of 3.676 (1) and 3.723 (1) Å]. The columns are linked by O-H⋯O and O-H⋯N hydrogen bonds, forming layers parallel to the ab plane. The layers are linked by C-H⋯O hydrogen bonds, forming a supra-molecular three-dimensional framework. An analysis of the Hirshfeld surfaces points to the importance of the O-H⋯O and O-H⋯N hydrogen bonding in the packing mechanism of the crystal structure.

Crystal structure and Hirshfeld surface analysis of N-[(2-hy-droxy-naphthalen-1-yl)(3-methyl-phen-yl)meth-yl]acetamide.

The title compound, C20H19NO2, is of inter-est as a precursor to biologically active substituted quinolines and related compounds. This compound crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. The dihedral angles between mean planes of the methyl-phenyl ring and the naphthalene ring system are 78.32 (6) and 84.70 (6)° in mol-ecules A and B, respectively. In the crystal, the anti-ferroelectric packing of mol-ecules A and B is of an ABBAABB type along the b-axis direction. The crystal structure features N-H⋯O, O-H⋯O and weak C-H⋯O hydrogen bonds, which link the mol-ecules into infinite chains propagating along the b-axis direction.