Synthesis, characterization and molecular docking studies of new indol(1H-3-yl)pyrimidine derivatives: Insights into their role in DNA interaction.

This study reports the synthesis of new indol(1H-3-yl) pyrimidine derivatives 4(a-e) using various substituted indole-3-carbaldehydes, urea and malononitrile in the presence of ammonium chloride. The resulting compounds were characterized using analytical and spectroscopic methods. The molecular docking study exhibits that among the synthesized compounds, 4(c-e) have great binding ability toward B-DNA. The binding efficiencies of compounds 4(c-e) with CT-DNA were evaluated via UV-visible absorption spectral and viscosity studies. The findings establish that the compounds firmly bind through an intercalative mode to CT-DNA and provide a unique pattern of DNA binding. The photo-induced cleavage indicates that the compounds have UV-visible photo nuclease properties toward plasmid DNA as revealed by agarose gel electrophoresis approach.

4-Chloro-2-[1-(4-ethyl-phen-yl)-4,5-diphenyl-1H-imidazol-2-yl]phenol.

In the title compound, C29H23ClN2O, the 5-chloro-phenol ring and the imidazole ring are nearly coplanar, with a dihedral angle of 15.76 (9)° between them. The ethyl-phenyl ring and the two phenyl rings subtend angles of 71.09 (7), 43.95 (5) and 36.53 (9)°, respectively, with the imidazole plane. An intra-molecular O-H⋯N hydrogen bond supports the mol-ecular conformation, and an inter-molecular C-H⋯O inter-action, originating from an ortho-phenyl H atom, stabilizes the packing arrangement. In addition, a weak C-H⋯π inter-action, also involving an ortho-phenyl H atom, is observed.

6-Methyl-4-{[4-(tri-methyl-sil-yl)-1H-1,2,3-triazol-1-yl]meth-yl}-2H-chromen-2-one.

In the title compound, C16H19N3O2Si, the dihedral angle between the coumarin ring system (r.m.s. deviation = 0.031 Å) and the triazole ring is 73.81 (8)°. In the crystal, mol-ecules are linked into [010] chains by weak C-H⋯O inter-actions.

4-Amino-6-(piperidin-1-yl)pyrimidine-5-carbo-nitrile.

In the title compound, C10H13N5, the piperidine ring adopts a chair conformation with the exocyclic N-C bond in an axial orientation, and the dihedral angle between the mean planes of piperidine and pyrimidine rings is 49.57 (11)°. A short intra-molecular C-H⋯N contact generates an S(7) ring. In the crystal, N-H⋯N hydrogen bonds link the mol-ecules into (100) sheets and a weak aromatic π-π stacking inter-action is observed [centroid-centroid separation = 3.5559 (11) Å] between inversion-related pyrimidine rings.

(2-Hy-droxy-phen-yl)(4,2':4',4''-terpyridin-6'-yl)methanone.

The title compound, C22H15N3O2, can be described as a ketone with a phenol substituent and a terpyridine ligand coordinated to the carbonyl group. The three six-membered rings of the terpyridine ligand are not coplanar. The dihedral angles between the mean planes of the central ring and the external pyridine ligands are 22.77 (9) and 26.77 (7)°. The central ring of the terpyridine ligand is also not coplanar with the o-hy-droxy phenyl ring, the dihedral angle being 39.72 (5)°. An intra-molecular O-H⋯O hydrogen bond occurs. The crystal structure of the title compound is consolidated by C-H⋯O and C-H⋯N hydrogen bonding inter-actions.

2-[1-(4-tert-Butyl-phen-yl)-4,5-diphenyl-1H-imid-azol-2-yl]-4,6-di-chloro-phenol.

In the title compound, C31H26Cl2N2O, the 4,6-di-chloro-phenol and the imidazole rings are almost coplanar, with a dihedral angle of 8.89 (6)° between them and an intra-molecular O-H⋯N hydrogen bond occurs between the rings. The dihedral angles subtended by the tert-butyl-phenyl ring and the two phenyl rings with the imidazole ring are 85.18 (9), 81.22 (9) and 19.00 (8)°, respectively. The methyl groups of the tert-butyl grouping are disordered over two sets of sites in 0.589 (5):0.411 (5) ratio. In the crystal, inversion dimers linked by pairs of weak C-H⋯Cl inter-actions generate R 2 2(24) loops.

Crystal structure of ethyl 4-(2-fluoro-phen-yl)-6-methyl-2-sulfanyl-idene-1,2,3,4-tetra-hydro-pyrimidine-5-carboxyl-ate.

The title compound, C14H15FN2O2S, crystallizes with two mol-ecules in the asymmetric unit. In each mol-ecule, the pyrimidine ring adopts a sofa conformation with the sp (3)-hybridized C atom forming the flap and the fluoro-substituted ring in an axial position. In the crystal, mol-ecules are linked via N-H⋯S hydrogen bonds, forming chains of R 2 (2)(8) rings along [100]. In one independent mol-ecule, an intra-molecular C-H⋯O hydrogen bond is observed.

Crystal structure of ethyl 5-acetyl-2-{[(di-methyl-amino)-methyl-idene]amino}-4-methyl-thio-phene-3-carboxyl-ate.

In the title thio-phene derivative, C13H18N2O3S, the dihedral angles between the thio-phene ring and the [(di-methyl-amino)-methyl-idene]amino side chain (r.m.s. deviation = 0.009 Å) and the -CO2 ester group are 3.01 (16) and 59.9 (3)°, respectively. In the crystal, inversion dimers linked by pairs of C-H⋯O hydrogen bonds generate R 2 (2)(16) loops. The dimers are linked by another weak C-H⋯O inter-action, forming chains along [001]. In addition, weak C-H⋯π inter-actions are observed, which link the chains into (001) layers.

Crystal structure of 2-acetyl-5-(3,4-di-meth-oxy-phen-yl)-6-eth-oxy-carbonyl-3,7-dimethyl-5H-thia-zolo[3,2-a]pyrimidin-8-ium chloride.

The title mol-ecular salt, C21H25N2O5S(+)·Cl(-), crystallizes with two ion pairs in the asymmetric unit. The cations have similar conformations (r.m.s. overlay fit = 0.40 Å), with one of them showing disorder of the terminal methyl group of the ester in a 0.72 (2):0.28 (2) ratio. In the first cation, the 3,4-dimeth-oxy-substituted phenyl ring subtends a dihedral angle of 88.38 (7)° with the pyrimidine ring and 6.79 (8)° with the thia-zole ring. The equivalent data for the second cation are 89.97 (3) and 6.42 (7)°, respectively. The pyrimidine ring adopts a sofa conformation in each cation. In the crystal, the components are linked by N-H⋯Cl hydrogen bonds, generating isolated ion pairs. The ion pairs are are linked by C-H⋯O inter-actions, generating a three-dimensional network. In addition, a weak C-H⋯π inter-action is observed.

Crystal structure of methyl 4-(2-fluoro-phenyl)-6-methyl-2-sulfanylidene-1,2,3,4-tetra-hydro-pyrimidine-5-carb-oxy-late.

In the title compound, C13H13FN2O2S, the pyrimidine ring adopts a twist-boat conformation with the MeCN and methine-C atoms displaced by 0.0938 (6) and 0.2739 (3) Å, respectively, from the mean plane through the other four atoms of the ring. The 2-fluoro-benzene ring is positioned axially and forms a dihedral angle of 89.13 (4)° with the mean plane through the pyrimidine ring. The crystal structure features N-H⋯O, N-H⋯S and C-H⋯O hydrogen bonds that link mol-ecules into supra-molecular chains along the b axis. These chains are linked into a layer parallel to (10-1) by C-H⋯π inter-actions; layers stack with no specific inter-actions between them.

Crystal structure of ethyl 2-acetyl-3,7-dimethyl-5-(thio-phen-2-yl)-5H-thia-zolo[3,2-a]pyrimidine-6-carboxyl-ate.

In the title compound, C17H18N2O3S2, the pyrimidine ring adopts a shallow sofa conformation, with the C atom bearing the axially-oriented thio-phene ring as the flap [deviation = 0.439 (3) Å]. The plane of the thio-phene ring lies almost normal to the pyrimidine ring, making a dihedral angle of 79.36 (19)°. In the crystal, pairs of very weak C-H⋯O hydrogen bonds link the mol-ecules related by twofold rotation axes, forming R 2 (2)(18) rings, which are in turn linked by another C-H⋯O inter-action, forming chains of rings along [010]. In addition, weak C-H⋯π(thio-phene) inter-actions link the chains into layers parallel to [001] and π-π inter-actions with a centroid-centroid distance of 3.772 (10) Šconnect these layers into a three-dimensional network.

Crystal structure of 4-azido-methyl-6-isopropyl-2H-chromen-2-one.

In the title mol-ecule, C13H13N3O2, the benzo-pyran ring system is essentially planar, with a maximum deviation of 0.017 (1) Å. In the crystal, weak C-H⋯O hydrogen bonds link mol-ecules into ladders along [010]. In addition, π-π inter-actions between inversion-related mol-ecules, with centroid-centroid distances in the range 3.679 (2)-3.876 (2) Å, complete a two-dimensional network parallel to (001).

Crystal structure of ethyl 2-cyano-3-[(1-eth-oxy-ethyl-idene)amino]-5-(3-meth-oxy-phen-yl)-7-methyl-5H-1,3-thia-zolo[3,2-a]pyrimidine-6-carboxyl-ate.

In the title compound, C22H24N4O4S, the central pyrimidine ring adopts a sofa conformation with the ring-junction N atom displaced by 0.2358 (6) Šfrom the mean plane of the remaining ring atoms. The 3-meth-oxy-phenyl ring, at the chiral C atom opposite the other N atom, is positioned axially and is inclined to the thia-zolo-pyrimidine ring with a dihedral angle of 83.88 (7)°. The thia-zole ring is essentially planar (r.m.s. deviation = 0.0034 Å). In the crystal, pairs of weak C-H⋯O hydrogen bonds link mol-ecules related by twofold rotation axes to form R 2 (2)(8) rings, which in turn are linked by weak C-H⋯N inter-actions, forming ribbons along [-110]. In addition, π-π stacking inter-actions [centroid-centroid distance = 3.5744 (15) Å] connect the ribbons, forming slabs lying parallel to (001).

Crystal structure of 2-(4-chloro-3-fluoro-phen-yl)-1H-benzimidazole.

In the title compound, C13H8ClFN2, the dihedral angle between the plane of the benzimidazole ring system (r.m.s. deviation = 0.022 Å) and the benzene ring is 26.90 (8)°. The F atom at the meta position of the benzene ring is disordered over two sites in a 0.843 (4):0.157 (4) ratio. In the crystal, mol-ecules are linked by N-H⋯N hydrogen bonds, forming infinite C(4) chains propagating along [010]. In addition, weak C-H⋯π and π-π inter-actions [shortest centroid-centroid separation = 3.6838 (12) Å] are observed, which link the chains into a three-dimensional network.

Crystal structure of ethyl 6-(2-fluoro-phen-yl)-4-hy-droxy-2-sulfanyl-idene-4-tri-fluoro-meth-yl-1,3-diazinane-5-carboxyl-ate.

In the title compound, C14H14F4N2O3S, the central di-hydro-pyrimidine ring adopts a sofa conformation with the C atom bearing the 2-fluoro-benzene ring displaced by 0.596 (3) Šfrom the other five atoms. The 2-fluoro-benzene ring is positioned axially and bis-ects the pyrimidine ring with a dihedral angle of 70.92 (8)°. The mol-ecular conformation is stabilized by an intra-molecular O-H⋯O hydrogen bond, generating an S(6) ring. The crystal structure features C-H⋯F, N-H⋯S and N-H⋯O hydrogen bonds, which link the mol-ecules into a three-dimensional network.

Crystal structure of ethyl 5-[3-(di-methyl-amino)-acrylo-yl]-2-{[(di-methyl-amino)-methyl-idene]-amino}-4-methylthio-phene-3-carb-oxy-late.

In the title compound, C16H23N3O3S, the dihedral angles between the thio-phene ring and the almost planar di-methyl-amino-methyl-ene-amino (r.m.s. deviation = 0.005 Å) and di-methyl-amino-acryloyl (r.m.s. deviation = 0.033 Å) substituents are 6.99 (8) and 6.69 (7)°, respectively. The ester CO2 group subtends a dihedral angle of 44.92 (18)° with the thio-phene ring. An intra-molecular C-H⋯O hydrogen bond generates an S(6) ring. In the crystal, inversion dimers linked by pairs of C-H⋯O hydrogen bonds generate R (2) 2(14) loops. In addition, a weak C-H⋯π inter-action is observed.

Crystal structure of ethyl 5-(3-fluoro-phen-yl)-2-[(4-fluoro-phen-yl)methyl-idene]-7-methyl-3-oxo-2H,3H,5H-[1,3]thia-zolo[3,2-a]pyrimidine-6-carboxyl-ate.

In the title mol-ecule, C23H18F2N2O3S, the pyrimidine ring is in a half-chair conformation and the 3-fluoro-phenyl group is in the axial position. The thia-zole ring (r.m.s. deviation = 0.0252 Å) forms dihedral angles of 84.8 (7) and 9.6 (7)° with the 3-fluoro-substituted and 4-fluoro-substituted benzene rings, respectively. In the crystal, weak C-H⋯F and C-H⋯O hydrogen bonds connect mol-ecules, forming zigzag chains along the b axis. In addition π-π stacking inter-actions with a centroid-centroid distance of 3.7633 (9) Šconnect these chains into ladders via inversion-related 4-fluoro-phenyl groups.

Crystal structure of 2-acetyl-5-(3-methoxyphenyl)-3,7-dimethyl-5H-1,3-thiazolo[3,2-a]pyrimidine-6-carboxylate.

In the title mol-ecule, C20H22N2O4S, the pyrimidine ring is in a flattened half-chair conformation and the 3-meth-oxyphenyl substituent is in an axial arrangement. The thia-zole ring forms a dihedral angle of 81.3 (1)° with the benzene ring. In the crystal, weak C-H⋯S inter-actions link mol-ecules into chains along [001]. In addition, there are π-π inter-actions between inversion-related thia-zole rings with a centroid-centroid distance of 3.529 (2) Å. The ethyl group was refined as disordered over two sets of sites with an occupancy ratio of 0.52 (3):0.48 (2).

2-[4-(Tri-fluoro-meth-yl)phen-yl]-1H-benzimidazole.

In the title compound, C14H9F3N2, the mean planes of the benzimidazole ring system and the tri-fluoro-methyl-substituted benzene ring form a dihedral angle of 30.1 (1)°. In the crystal, mol-ecules are linked by N-H⋯N hydrogen bonds into chains along [010]. Weak C-H⋯F hydrogen bonds and a weak C-H⋯π inter-action connect the chains into a two-dimensional network parallel to (001).

Methyl 4-(4-hy-droxy-phen-yl)-6-methyl-2-sulfanyl-idene-1,2,3,4-tetra-hydro-pyrimidine-5-carboxyl-ate.

In the title mol-ecule, C13H14N2O3S, the di-hydro-pyrimidine ring is in a flattened sofa conformation, with the methine C atom forming the flap. The dihedral angle between the mean plane of the five essentially planar atoms of the di-hydro-pyrimidine ring [maximum deviation = 0.056 (4) Å] and the benzene ring is 89.4 (2)°. The O atom of the carbonyl group is in a trans conformation with respect to the C=C bond of the di-hydro-pyrimidine ring. In the crystal, N-H⋯O and O-H⋯S hydrogen bonds connect mol-ecules, forming a two-dimensional network parallel to (001).