Tetrazolylmethyl quinolines: Design, docking studies, synthesis, anticancer and antifungal analyses.

A new series of 2,5 and 1,5-regioisomers of the tetrazolyl group viz., 3-[(5-benzyl/benzylthio-2H-tetrazol-2-yl) methyl]-2-chloro-6-substituted quinoline 6h-q and 3-[(5-benzyl/benzylthio-1H-tetrazol-1-yl) methyl]-2-chloro-6-substituted quinolines 7h-q were synthesized. Docking studies of all these compounds with DNA as target using PDB: 1AU5 and 453D revealed that the compounds 6h and 6i act as covalent cross linker on the DNA helix of the former and intercalate the latter both with higher C score values. Another set of docking studies in the active pocket of dihydrofolate reductase and N-myristoyl transferase as targets to assess antifungal activity revealed that compounds 6k, 6l, 6p and 7q (with bromo and fluro substituents) showcases different binding modes and hydrogen bonding. Further, the compounds were screened for anticancer activity (primary cytotoxicity) against NCI-60 Human tumor cell line at a single high dose (10-5 M) concentration assay. Among the tested compounds, 6h has shown 99.28% of GI against Melanoma (SK-MEL-5) and compound 6i has shown 97.56% of GI against Breast Cancer (T-47D). Further, in vitro antifungal assay against A. fumigatus and C. albicans for these compounds 6h-q and 7h-q revealed potential to moderate activities as compared to the standard.

Synthesis, anti-proliferative and genotoxicity studies of 6-chloro-5-(2-substituted-ethyl)-1,3-dihydro-2H-indol-2-ones and 6-chloro-5-(2-chloroethyl)-3-(alkyl/ary-2-ylidene)indolin-2-ones.

A series of 6-chloro-5-(2-substituted-ethyl)-1,3-dihydro-2H-indol-2-ones (3a-h) and 6-chloro-5-(2-chloroethyl)-3-(alkyl/aryl-2-ylidene)indolin-2-ones (5i-x) were synthesized. Compounds 3a-e, 5i-l and 5q-r were selected by NIH, USA for in vitro anti-proliferative screening. Based on the impressive growth inhibitory (GI %) effect by the compounds 3a-b and 3e which showed growth inhibition in the range 1.22-76.30%, 2.85-76.03% and 10.98-82.05% respectively at 10(-5) concentration, these compounds were further analyzed for anti-proliferative activity at 5 dose concentration and genotoxicity.

Crystal structure of 6-chloro-5-(2-chloro-eth-yl)-3-(propan-2-yl-idene)indolin-2-one.

The title compound, C13H13Cl2NO, has a 3-(propan-2-yl-idene)indolin-2-one core with a Cl atom and a chloro-ethyl substituent attached to the aromatic ring. Two atoms of the aromatic ring and the chloro-ethyl substituent atoms are disordered over two sets of sites with a refined occupancy ratio of 0.826 (3):0.174 (3). In the crystal, mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers with an R 2 (2)(8) ring motif.

Crystal structure of diethyl 2-[(2-sulfan-yl-quinolin-3-yl)methyl-idene]malonate.

In the title compound, C17H17N O4S, the quinoline ring system is nearly planar, with a maximum deviation of 0.0496 (16) Å. A weak intra-molecular C-H⋯O inter-action is observed. In the crystal, C-H⋯O, S-H⋯N and π-π stacking inter-actions between the fused benzene ring of quinoline and the pyridine moieties [shortest centroid-centroid distance = 3.6754 (11) Å] are observed. Inversion-related weak C-H⋯O inter-molecular inter-actions diagonally along [010], with R 2 (2)(10) ring motifs, and S-H⋯N inter-molecular inter-actions diagonally along [100], with R 2 (2)(8) ring motifs, are present, forming a three-dimensional network structure. No classical hydrogen bonds are observed.

Crystal structure of (7-methyl-2-oxo-2H-chromen-4-yl)methyl piperidine-1-carbo-di-thio-ate.

In the title compound, C17H19NO2S2, the 2H-chromene ring system is nearly planar, with a maximum deviation of 0.0383 (28) Å, and the piperidine ring adopts a chair conformation. The 2H-chromene ring makes dihedral angles of 32.89 (16) and 67.33 (8)°, respectively, with the mean planes of the piperidine ring and the carbodi-thio-ate group. In the crystal, C-H⋯O and weak C-H⋯S hydrogen bonds link the mol-ecules into chains along [001]. The crystal structure also features C-H⋯π and π-π inter-actions, with a centroid-centroid distance of 3.7097 (17) Å.

Crystal structure of (6-bromo-2-oxo-2H-chromen-4-yl)methyl morpholine-4-carbodi-thio-ate.

In the title compound, C15H14BrNO3S2, the 2H-chromene ring system is nearly planar, with a maximum deviation of 0.034 (2) Å, and the morpholine ring adopts a chair conformation. The dihedral angle between best plane through the 2H-chromene ring system and the morpholine ring is 86.32 (9)°. Intra-molecular C-H⋯S hydrogen bonds are observed. In the crystal, inversion-related C-H⋯S and C-H⋯O inter-actions generate R 2 (2)(10) and R 2 (2)(8) rings patterns, respectively. In addition, the crystal packing features π-π inter-actions between fused benzene rings [centroid-centroid distance = 3.7558 (12) Å].

Crystal structure of 5-(1-benzo-furan-2-yl)-3-(4-methyl-phen-yl)-4,5-di-hydro-1,2-oxazol-5-ol.

In the title compound, C18H15NO3, the isoxazole moiety adopts a shallow envelope conformation, with the C atom bearing the OH group displaced by 0.148 (1) Šfrom the mean plane through the other four atoms. The mean plane of this ring (all atoms) subtends dihedral angles of 87.19 (6) and 15.51 (7)° with the benzo-furan ring system (r.m.s. deviation = 0.007 Å) and the 4-methylphenyl ring, respectively. In the crystal, mol-ecules are linked by O-H⋯N hydrogen bonds, generating [001] C(5) chains, with adjacent mol-ecules in the chain related by c-glide symmetry. Weak C-H⋯O inter-actions link the chains into a three-dimensional network.

Crystal structure of (7-chloro-2-oxo-2H-chromen-4-yl)methyl N,N-di-methyl-carbamodi-thio-ate.

In the title compound, C13H12Cl N O2S2, the 2H-chromene ring system is almost planar, with a maximum deviation of 0.005 (2) Å. The packing features C-H⋯S hydrogen bonds and π-π inter-actions between fused benzene rings of chromene [shortest centroid-centroid distances = 3.6553 (13) and 3.5551 (13) Å].

Crystal structure of 4-meth-oxy-phenyl 2-oxo-2H-chromene-3-carboxyl-ate.

In the title compound, C17H12O5, the dihedral angle between the planes of the coumarin ring system (r.m.s. deviation = 0.015 Å) and the benzene ring is 48.04 (10)°. The central CO2 group subtends a dihedral angle of 27.15 (11)° with the coumarin ring system and 74.86 (13)° with the benzene ring. In the crystal, mol-ecules are linked by C-H⋯O inter-actions, which generate a three-dimensional network. Very weak C-H⋯π inter-actions are also observed.

Crystal structure of 4-bromo-phenyl-2-oxo-2H-chromene-3-carboxyl-ate.

In the title compound, C16H9BrO4, the coumarin ring system is approximately planar, with an r.m.s deviation of the ten fitted non-H atoms of 0.031 Å, and forms a dihedral angle of 25.85 (10)° with the bromo-benzene ring. The carbonyl atoms are syn. In the crystal, mol-ecules are connected along [001] via C-H⋯O inter-actions, forming C(6) chains. Neighbouring C(6) chains are connected via several π-π inter-actions [range of centroid-centroid distances = 3.7254 (15)-3.7716 (16) Å], leading to sheets propagating in the bc plane.

Crystal structure of bis-(4-meth-oxy-phenyl) malonate.

The complete mol-ecule of the title compound, C17H16O6, is generated by crystallographic twofold symmetry, with the central methyl-ene C atom lying on the rotation axis. The carbonyl O atom is disordered over two adjacent positions in a 0.63 (3):0.37 (3) ratio and the dihedral angle between the benzene rings in the two halves of the mol-ecule is 79.31 (12)°. In the crystal, mol-ecules are connected by C-H⋯O hydrogen bonds, generating (110) sheets. Very weak intra-sheet C-H⋯π inter-actions are also observed.

Crystal structure of (7-fluoro-2-oxo-2H-chromen-4-yl)methyl morpholine-4-carbodi-thio-ate.

In the title compound, C15H14FNO3S2, the 2H-chromene ring system is close to being planar (r.m.s. deviation = 0.024 Å) and the morpholine ring adopts a chair conformation. The dihedral angle between the 2H-chromene ring system and the morpholine ring (all atoms) is 88.21 (11)°. In the crystal, inversion dimers linked by pairs of very weak C-H⋯F hydrogen bonds generate R 2 (2)(8) loops; C-H⋯O hydrogen bonds connect the dimers into [010] chains. Weak aromatic π-π stacking inter-actions between the pyran rings of the chromene systems [centroid-centroid distance = 3.6940 (16) Å] are also observed.

Crystal structure of (2E)-1-(5-bromo-thio-phen-2-yl)-3-(2-chloro-phen-yl)prop-2-en-1-one.

In the title compound, C13H8BrClOS, the thienyl ring is not coplanar with the benzene ring, their planes forming a dihedral angle of 13.2 (4)°. In the crystal, mol-ecules stack along the a axis, with the inter-planar separation between thienyl rings and between benzene rings being 3.925 (6) Å. The sample is an inversion twin.

tert-Butyl 2-{[5-(4-cyano-phen-yl)pyridin-3-yl]sulfon-yl}acetate.

In the title compound, C18H18N2O4S, the dihedral angle between the aromatic rings is 33.71 (9)° and an intra-molecular C-H⋯O hydrogen bond closes an S(6) ring. In the crystal, mol-ecules are linked by C-H⋯O and C-H⋯N hydrogen bonds to generate a three-dimensional network. A very weak aromatic π-π stacking inter-ction is also observed [centroid-centroid separation = 3.9524 (10) Å].

N-(6-Chloro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)benzene-sulfonamide.

The asymmetric unit of the title compound, C13H11ClN4O2S, contains two mol-ecules (A and B), in which the dihedral angles between the 1H-imidazo[4,5-c]pyridine system and terminal phenyl ring are 80.83 (10) and 62.34 (1)°. In the crystal, A-B dimers are linked by pairs of N-H⋯N hydrogen bonds, which generate R (2) 2(10) loops. The dimers are linked by C-H⋯O and C-H⋯Cl inter-actions, generating a three-dimensional network. Aromatic π-π stacking inter-actions [shortest centroid-centroid distance = 3.5211 (12) Å] are also observed.

1,1',1'',1'''-(Oxydi-methane-tri-yl)tetra-kis-(4-fluoro-benzene).

In the title compound, C26H18F4O2, the dihedral angles between pairs of benzene rings linked to the same C atom are 80.55 (8) and 79.11 (7)°. The crystal packing features C-H⋯π inter-actions and shows stacking when viewed along the c axis.

1-(4-Chloro-phen-yl)-1H-1,2,4-triazol-5(4H)-one.

In the title compound, C8H6ClN3O, the dihedral angle between the 1,2,4-triazole and benzene rings is 4.60 (9)° and an intra-molecular C-H⋯O inter-action closes an S(6) ring. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R 2 (2)(8) loops and C-H⋯O inter-actions link the dimers into [100] chains. Weak π-π stacking inter-actions [centroid-centroid distance = 3.644 (1) Å] are also observed.

1-(6-Chloro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-3-(2-chloro-phen-yl)urea.

In the title compound, C14H11Cl2N5O, the plane of the 1H-imidazo[4,5-c]pyridine ring system [r.m.s. deviation = 0.087 (19) Å] makes a dihedral angle of 4.87 (10)° with the terminal phenyl ring. An intra-molecular N-H⋯N hydrogen bond stabilizes the mol-ecular conformation. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into inversion dimers. These dimers are connected by π-π inter-actions between imidazole rings [shortest centroid-centroid distance = 3.4443 (14) Å].

Ethyl (4-{[(di-ethyl-carbamo-thio-yl)sulfan-yl]meth-yl}-2-oxo-2H-chromen-7-yl)carbamate.

In the title compound, C18H22N2O4S2, the 2H-chromene ring system is essentially planar (r.m.s. deviation = 0.012 Å). The mol-ecular conformation is stabilized by a C-H⋯O hydrogen bond. In the crystal, N-H⋯S and C-H⋯O hydrogen bonds occur, the former enclosing an R (2) 2(22) ring motif, and lead to the formation of a two-dimensional slab-like network lying parallel to (10-1). π-π inter-actions are observed between inversion-related aromatic rings [shortest centroid-centroid distance = 3.6300 (11) Å].

6-(4-Fluoro-phen-yl)-3-phenyl-7H-1,2,4-tri-azolo[3,4-b][1,3,4]thia-diazine.

In the title compound, C16H11FN4S, the dihedral angles between the triazole ring and the phenyl and fluoro-benzene rings are 23.22 (17) and 18.06 (17)°, respectively. The six-membered heterocyclic ring adopts a distorted envelope conformation, with the methyl-ene C atom as the flap. In the crystal, the mol-ecules are linked by two C-H⋯N and C-H⋯F inter-actions along [010], forming C(5), C(8) and C(13) chains repectively. C-H⋯π inter-actions involving the phenyl ring and π-π inter-actions [centroid-centroid separation for triazole rings = 3.5660 (18) Å] are also observed.