Crystal structure of N-(1-allyl-3-chloro-4-eth-oxy-1H-indazol-5-yl)-4-meth-oxybenzene-sulfonamide.

In the title compound, C19H20ClN3O4S, the benzene ring is inclined to the indazole ring system (r.m.s. deviation = 0.014 Å) by 65.07 (8)°. The allyl and eth-oxy groups are almost normal to the indazole ring, as indicated by the respective torsion angles [N-N-C-C = 111.6 (2) and C-C-O-C = -88.1 (2)°]. In the crystal, mol-ecules are connected by N-H⋯N hydrogen bonds, forming helical chains propagating along [010]. The chains are linked by C-H⋯O hydrogen bonds, forming a three-dimensional network.

Crystal structure of N-(1-allyl-3-chloro-1H-indazol-5-yl)-4-methyl-benzene-sulfonamide.

The 3-chloro-1H-indazole system in the title mol-ecule, C17H16ClN3O2S, is almost planar, with the largest deviation from the mean plane being 0.029 (2) Šfor one of the N atoms. This system is nearly perpendicular to the allyl chain, as indicated by the C-C-N-N torsion angle of -90.1 (6)° between them. The allyl group is split into two fragments, the major component has a site occupancy of 0.579 (7). The indazole system makes a dihedral angle of 47.53 (10)° with the plane through the benzene ring. In the crystal, mol-ecules are connected by N-H⋯O and C-H⋯O hydrogen bonds, forming a three-dimensional network.

Crystal structure of N-(3-chloro-1-methyl-1H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide.

In the title compound, C15H14ClN3O3S, the dihedral angle between the planes of the indazole ring system (r.m.s. deviation = 0.007 Å) and the benzene ring is 89.05 (7)°. The meth-oxy C atom deviates from its attached ring by 0.196 (3) Å. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R 2 (2)(8) loops. The dimers are connected into [010] chains by C-H⋯O inter-actions.

N-(1-Allyl-3-chloro-4-eth-oxy-1H-indazol-5-yl)-4-methyl-benzene-sulfonamide.

In the title compound, C19H20ClN3O3S, the benzene ring is inclined to the indazole ring system by 51.23 (8)°. In the crystal, mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers which stack in columns parallel to [011]. The atoms in the allyl group are disordered over two sets of sites with an occupancy ratio of 0.624 (8):0.376 (8).

N-(3-Chloro-4-eth-oxy-1-methyl-1H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide.

The indazole ring system of the title compound, C17H18ClN3O4S, is almost planar (r.m.s. deviation = 0.0113 Å) and forms dihedral angles of 32.22 (8) and 57.5 (3)° with the benzene ring and the mean plane through the 4-eth-oxy group, respectively. In the crystal, mol-ecules are connected by pairs of N-H⋯O hydrogen bonds into inversion dimers, which are further linked by π-π inter-actions between the diazole rings [inter-centroid distance = 3.4946 (11) Å], forming chains parallel to [101].

N-(2-Allyl-4-eth-oxy-2H-indazol-5-yl)-4-methyl-benzene-sulfonamide.

The indazole ring system of the title compound, C19H21N3O3S, is almost planar (r.m.s. deviation = 0.0192 Å) and forms dihedral angles of 77.99 (15) and 83.9 (3)° with the benzene ring and allyl group, respectively. In the crystal, centrosymmetrically related mol-ecules are connected by pairs of N-H⋯O hydrogen bonds into dimers, which are further linked by C-H⋯O hydrogen bonds, forming columns parallel to the b axis.

N-(3-Chloro-1-methyl-1H-indazol-5-yl)-4-methylbenzene-sulfonamide.

The asymmetric unit of the title compound, C15H14ClN3O2S, contains two independent mol-ecules showing different conformations: in one mol-ecule, the indazole ring system makes a dihedral angle of 51.5 (1)° with the benzene ring whereas in the other, the indazole unit is almost perpendicular to the benzene ring [dihedral angle 77.7 (1)°]. In the crystal, the mol-ecules are linked by N-H⋯N and N-H⋯O hydrogen bonds, forming a set of four mol-ecules linked in pairs about an inversion centre.

Synthesis and antitumor activity of some substituted indazole derivatives.

Some new N-[6-indazolyl]arylsulfonamides and N-[alkoxy-6-indazolyl]arylsulfonamides were prepared by the reduction of 2-alkyl-6-nitroindazoles with SnCl2 in different alcohols, followed by coupling the corresponding amine with arylsulfonyl chlorides in pyridine. The newly synthesized compounds were evaluated for their antiproliferative and apoptotic activities against two human tumor cell lines: A2780 (ovarian carcinoma) and A549 (lung adenocarcinoma). Preliminary in vitro pharmacological studies revealed that N-(2-allyl-2H-indazol-6-yl)-4-methoxybenzenesulfonamide 4 and N-[7-ethoxy-2-(4-methyl-benzyl)-2H-indazol-6-yl]-4-methyl-benzenesulfonamide 9 exhibited significant antiproliferative activity against the A2780 and A549 cell lines with IC50 values in the range from 4.21 to 18.6 µM, and also that they trigger apoptosis in a dose-dependent manner. Furthermore, both active compounds were able to cause an arrest of cells in the G2/M phase of the cell cycle, typical but not exclusive of tubulin interacting agents, although only infrequent interactions with the microtubule network were observed by immunofluorescence microscopy, while docking analysis showed a possible different behavior between the two active compounds.

N-(2-Allyl-4-chloro-2H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide hemi-hydrate.

The fused five- and six-membered rings in the title compound, C17H16ClN3O3S·0.5H2O, are practically coplanar, with the maximum deviation from the mean plane being 0.057 (3) Šfor the C atom bound to the exocyclic N atom. The indazole system makes a dihedral angle of 66.18 (12)° with the plane through the benzene ring, and it is nearly perpendicular to the allyl group, as indicated by the N-N-C-C torsion angle of 79.2 (3)°. In the crystal, the water mol-ecule, lying on a twofold axis, forms O-H⋯N and accepts N-H⋯O hydrogen bonds. Additional C-H⋯O hydrogen bonds contribute to the formation of a chain along the b-axis direction.

N-(1-Allyl-1H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide hemihydrate.

In the title compound, C17H17N3O3 (.)0.5H2O, the indazole system makes a dihedral angle of 46.19 (8)° with the plane through the benzene ring and is nearly perpendicular to the allyl group, as indicated by the dihedral angle of 81.2 (3)°. In the crystal, the water mol-ecule, disordered over two sites related by an inversion center, forms O-H⋯N bridges between indazole N atoms of two sulfonamide mol-ecules. It is also connected via N-H⋯O inter-action to the third sulfonamide mol-ecule; however, due to the water mol-ecule disorder, only every second mol-ecule of sulfonamide participates in this inter-action. This missing inter-action results in a slight disorder of the sulfonamide S,O and N atoms which are split over two sites with half occupancy. With the help of C-H⋯O hydrogen bonds, the mol-ecules are further connected into a three-dimensional network.

N-(3-Chloro-1H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide.

In the title compound, C14H12ClN3O3S, the fused five- and six-membered rings are folded slightly along the common edge, forming a dihedral angle of 3.2 (1)°. The mean plane through the indazole system makes a dihedral angle of 30.75 (7)° with the distant benzene ring. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules, forming a two-dimensional network parallel to (001).

N-(1H-Indazol-5-yl)-4-meth-oxy-benzene-sulfonamide.

In the title compound, C14H13N3O3S, the fused ring system is almost planar, the largest deviation from the mean plane being 0.023 (2) Å, and makes a dihedral angle of 47.92 (10)° with the benzene ring of the benzene-sulfonamide moiety. In the crystal, mol-ecules are connected through N-H⋯O hydrogen bonds and weak C-H⋯O contacts, forming a two-dimensional network which is parallel to (010).

4-Meth-oxy-N-(1-methyl-1H-indazol-5-yl)benzene-sulfonamide.

The indazole ring system [maximum deviation = 0.013 (2) Å] of the title compound, C15H15N3O3S, makes a dihedral angle of 50.11 (7)° with the benzene ring. In the crystal, cohesion is provided by C-H⋯O and N-H⋯N hydrogen bonds, which link the molecules into chains propagating along the b-axis direction.

1-Allyl-3-chloro-5-nitro-1H-indazole.

In the title compound, C10H8ClN3O2, the indazole ring system makes a dihedral angle of 7.9 (3)° with the plane through the nitro group. The allyl group is rotated out of the plane of the indazole ring system [N-N-C-C torsion angle = 104.28 (19)°]. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, forming zigzag chains propagating along the b-axis direction.

4-Methyl-N-(1-methyl-1H-indazol-5-yl)benzene-sulfonamide.

In the title compound, C15H15N3O2S, the fused ring system is close to planar, the largest deviation from the mean plane being 0.030 (2) Å, and makes a dihedral angle of 48.84 (9)° with the benzene ring belonging to the methyl-benzene-sulfonamide moiety. In the crystal, mol-ecules are -connected through N-H⋯N hydrogen bonds and weak C-H⋯O contacts, forming a two-dimensional network parallel to (001).

N-(1-Allyl-1H-indazol-5-yl)-4-methyl-benzene-sulfonamide.

The asymmetric unit of the title compound, C17H17N3O2S, contains two independent mol-ecules linked by an N-H⋯O hydrogen bond. The mol-ecules show different conformations. In the first mol-ecule, the fused five- and six-membered ring system is almost perpendicular to the plane through the atoms forming the allyl group, as indicated by the dihedral angle of 85.1 (4)°. The dihedral angle with the methyl-benzene-sulfonamide group is 78.8 (1)°. On the other hand, in the second mol-ecule, the dihedral angles between the indazole plane and the allyl and methyl-benzene-sulfonamide groups are 80.3 (3) and 41.5 (1)°, respectively. In the crystal, mol-ecules are further linked by N-H⋯N and C-H⋯O hydrogen bonds, forming a three-dimensional network.

Synthesis, antiproliferative and apoptotic activities of N-(6(4)-indazolyl)-benzenesulfonamide derivatives as potential anticancer agents.

Recently, it has been reported that compounds bearing a sulfonamide moiety possess many types of biological activities, including anticancer activity. The present work reports the synthesis and antiproliferative evaluation of some N-(6(4)-indazolyl)benzenesulfonamides and 7-ethoxy-N-(6(4)-indazolyl)benzenesulfonamides. All compounds were evaluated for their in vitro antiproliferative activity against three tumor cell lines: A2780 (human ovarian carcinoma) A549 (human lung adenocarcinoma) and P388 (murine leukemia). The results indicated that sulfonamides 2c, 3c, 6d, 8, 13, 3b and 16 were endowed with a pharmacologically interesting antiproliferative activity with compounds 2c and 3c showing the lower IC(50) (from 0.50 ± 0.09 to 1.83 ± 0.52 µM and from 0.58 ± 0.17 to 5.83 ± 1.83 µM, respectively). Moreover, these indazoles were able to trigger apoptosis through the upregulation of the typical apoptosis markers p53 and bax. As regard to the hypothetic targets of these compounds, a preliminary docking analysis showed that all compounds seemed to interact with ß-tubulin, in particular compound 3b that showed the lower Ki. The cytofluorimetric analysis of the cell cycle phases indicates that all compounds, when administered at their IC(75), caused a block in the G2/M phase of the cell cycle with the generation of subpopulations of cells with a number of chromosome >4n. When the IC(50)s were applied we observed a prevalent block in the G0/G1 phase except for compounds 16 and 8 where a partial G2/M block was present with a concomitant decrease of cells in the G0/G1 and S phases of the cell cycle. Altogether these results suggest a possible, but not exclusive, interaction with microtubules.