N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-methoxybenzamide: design, synthesis, crystal structure, antiproliferative activity, DFT, Hirshfeld surface analysis and molecular docking study.

The compound N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-methoxybenzamide (8) was synthesized by the condensation of 3-methoxybenzoic acid (7) with N1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)ethane-1,2-diamine (6). This intermediate was prepared from methyl 3-aminothiophene-2-carboxylate (1) by the condensation with urea, chlorination with phosphorus oxychloride and then condensation with ethane-1,2-diamine. The crystal structure of the title compound was determined and the crystal of the title compound belongs to the tetragonal system, space group P4(3) with a = 9.4694(10) Å, b = 9.4694(10) Å, c = 18.886(3) Å, α = 90°, ß = 90°, γ = 90°. The optimized geometric bond lengths and bond angles obtained by using density functional theory (DFT) have been compared with X-ray diffraction values. The calculated HOMO and LUMO energies showed the character of the title compound. The molecular electrostatic potential (MEP) surface map of the related molecule was investigated with theoretical calculations at the B3LYP/6-311 + G(d,p) levels. A quantitative analysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld surface analysis. In addition, the title compound possesses marked inhibition against the proliferation of human colon cancer cell line HT-29 (IC50 = 1.76 µM), human lung adenocarcinoma cell line A549 (IC50 = 1.98 µM) and human gastric cancer cell line MKN45 (IC50 = 2.32 µM), displaying promising anticancer activitiy. The molecular docking studies revealed that the title compound may exhibit activity inhibiting PDB:3D15.Communicated by Ramaswamy H. Sarma.

4-Hy-droxy-N'-[1-(2-hy-droxy-phen-yl)ethyl-idene]benzohydrazide.

In the title compound, C(15)H(14)N(2)O(3), there is an intra-molecular O-H⋯N hydrogen bond and the dihedral angle between the two aromatic rings is 13.9 (3)°. In the crystal structure, mol-ecules are stabilized by inter-molecular O-H⋯O and N-H⋯O hydrogen bonds.

N'-[1-(2-Hy-droxy-phen-yl)ethyl-idene]-2-meth-oxy-benzohydrazide.

There are two independent mol-ecules in the asymmetric unit of the title compound, C(16)H(16)N(2)O(3), in which the dihedral angles between the two aromatic rings are 13.0 (3) and 6.4 (3)°. Intra-molecular O-H⋯N and N-H⋯O hydrogen bonds are observed in both mol-ecules, forming S(6) rings in all cases.

Dibromido{2-[1-(cyclo-propyl-imino)-eth-yl]pyridine}-zinc(II).

In the title compound, [ZnBr(2)(C(10)H(12)N(2))], the Zn(2+) ion is coordinated by the N,N'-bidentate Schiff base ligand and two bromode ions in a distorted tetra-hedral arrangement. The dihedral angle between the pyridine and the cyclo-propyl rings is 95.4 (8)°.

Bis[2-(cyclo-pentyl-imino-meth-yl)-5-meth-oxy-phenolato]copper(II).

The title compound, [Cu(C(13)H(16)NO(2))(2)], is a mononuclear copper(II) complex derived from the Schiff base ligand 2-(cyclo-pentyl-imino-meth-yl)-5-meth-oxy-phenol and copper acetate. The Cu(II) atom is four-coordinated by the phenolate O atoms and imine N atoms from two Schiff base ligands, in a highly distorted square-planar geometry. The O- and N-donor atoms are mutually trans and the dihedral angle between the two benzene rings is 55.8 (3)°.

Bis{1-[3-(diethyl-ammonio)-propyl-imino-meth-yl]naphthalen-2-olato}nickel(II) dinitrate.

The asymmetric unit of the title compound, [Ni(C(18)H(24)N(2)O)(2)](NO(3))(2), consists of one half of the centrosymmetric nickel(II) complex cation and a nitrate anion. The Ni(II) atom, lying on an inversion center, is four-coordinated by the phenolate O atoms and imine N atoms of two Schiff base ligands, forming a square-planar geometry. The O- and N-donor atoms are mutually trans. In the crystal structure, the nitrate anions are linked to the complex cations by inter-molecular N-H⋯O hydrogen bonds.

{2-[2-(Isopropyl-amino)-ethyl-imino-meth-yl]-5-meth-oxy-phenolato}(thio-cyanato--κN)nickel(II).

In the title mononuclear complex, [Ni(C(13)H(19)N(2)O(2))(NCS)], the Ni(II) ion is coordinated by one phenolate O atom, one imine N atom, and one amine N atom of a 2-[2-(isopropyl-amino)-ethyl-imino-meth-yl]-5-meth-oxy-phenolate Schiff base ligand, and by one N atom of a thio-cyanate ligand, forming a slightly distorted square-planar geometry.

N'-(5-Bromo-2-hydr-oxy-3-methoxy-benzyl-idene)-4-hydr-oxy-3-methoxy-benzohydrazide dihydrate.

In the title compound, C(16)H(15)BrN(2)O(5)·2H(2)O, the dihedral angle between the two aromatic rings is 2.9 (2)° and an intra-molecular O-H⋯N hydrogen bond is observed. One of the water mol-ecule is disordered over two positions, with occupancies of 0.83 (3) and 0.17 (3). In the crystal structure, mol-ecules are linked into a three-dimensional network by inter-molecular O-H⋯O, O-H⋯(O,O), O-H⋯N and N-H⋯O hydrogen bonds. π-π inter-actions involving Br-substituted benzene rings, with a centroid-centroid distance of 3.552 (3) Šare also observed.

N'-(4-Hydr-oxy-3-methoxy-benzyl-idene)-4-methoxy-benzohydrazide monohydrate.

In the title compound, C(16)H(16)N(2)O(4)·H(2)O, the dihedral angle between the two aromatic rings is 19.6 (2)°. In the crystal structure, mol-ecules are linked into a three-dimensional network by inter-molecular N-H⋯O, O-H⋯N and O-H⋯O hydrogen bonds.

N'-(3-Eth-oxy-2-hydroxy-benzyl-idene)-4-hydr-oxy-3-methoxy-benzohydrazide monohydrate.

In the title compound, C(17)H(18)N(2)O(5)·H(2)O, the dihedral angle between the two aromatic rings is 7.86 (7)° and an intra-molecular O-H⋯N hydrogen bond is observed. In the crystal structure, mol-ecules are linked into a three-dimensional network by inter-molecular O-H⋯O and N-H⋯O hydrogen bonds.

4-Hydr-oxy-N'-(2-hydr-oxy-3-methoxy-benzyl-idene)benzohydrazide mono-hydrate.

In the title compound, C(15)H(14)N(2)O(4)·H(2)O, the dihedral angle between the two aromatic rings is 33.3 (5)°. The meth-oxy group is twisted slightly away from the attached benzene ring [C-O-C-C = 13.8 (9)°]. An intra-molecular O-H⋯N hydrogen bond is observed. In the crystal structure, the mol-ecules are linked into a two-dimensional network parallel to the (010) plane by inter-molecular N-H⋯O, O-H⋯O and C-H⋯O hydrogen bonds.

N'-[4-(Dimethyl-amino)-benzyl-idene]-4-meth-oxybenzohydrazide.

The title Schiff base compound, C(17)H(19)N(3)O(2), was obtained from the condensation of 4-dimethyl-amino-benzaldehyde with 4-methoxy-benzohydrazide in an ethanol solution. The mol-ecule is twisted with respect to the N-N single bond [C-N-N-C = -159.27 (14)°] and the dihedral angle between the two aromatic rings is 67.1 (2)°. In the crystal structure, the mol-ecules are linked into chains along the c axis by inter-molecular N-H⋯O and C-H⋯O hydrogen bonds.

N'-(5-Bromo-2-methoxy-benzyl-idene)-2-hydroxy-benzohydrazide.

The title Schiff base compound, C(15)H(13)BrN(2)O(3), is derived from the condensation of 5-bromo-2-methoxy-benzaldehyde with 2-hydroxy-benzohydrazide in an ethanol solution. The dihedral angle between the two aromatic rings is 6.9 (9)°. The meth-oxy group is coplanar with the attached ring [C-O-C-C = 3.1 (12)°]. An intra-molecular N-H⋯O hydrogen bond is observed. In the crystal structure, the mol-ecules are linked into chains along the [001] direction by inter-molecular O-H⋯N, O-H⋯O and C-H⋯O hydrogen bonds.

N'-(2-Hydroxy-benzyl-idene)-2-methoxy-benzohydrazide monohydrate.

In the title compound, C(15)H(14)N(2)O(3)·H(2)O, the Schiff base mol-ecule is approximately planar, with a dihedral angle between the two aromatic rings of 10.2 (3)°. The mol-ecular structure is stabilized by O-H⋯N and N-H⋯O hydrogen bonds. In the crystal structure, the Schiff base and water mol-ecules are linked together by inter-molecular O-H⋯O hydrogen bonds, forming chains parallel to the a axis.

4-Chloro-N'-(2-hydroxy-benzyl-idene)benzohydrazide monohydrate.

The asymmetric unit of the title compound, C(14)H(11)ClN(2)O(2)·H(2)O, contains a Schiff base mol-ecule and a water mol-ecule of crystallization. The dihedral angle between the two aromatic rings is 27.3 (4)°. In the crystal structure, mol-ecules are linked into a two-dimensional network parallel to the bc plane by inter-molecular O-H⋯O and N-H⋯O hydrogen bonds involving the water mol-ecules.

2-Meth-oxy-N'-(2-methoxy-benzyl-idene)benzohydrazide.

The title Schiff base compound, C(16)H(16)N(2)O(3), was derived from the condensation of 2-methoxy-benzaldehyde with 2-methoxy-benzohydrazide in an ethanol solution. The dihedral angle between the two aromatic rings is 87.5 (3)°. In the crystal structure, the mol-ecules are linked into chains running parallel to the a axis by inter-molecular N-H⋯O hydrogen bonds.