Indole Ring System Research Articles

Detection of the recently emerged synthetic cannabinoid 5F–MDMB‐PICA in ‘legal high’ products and human urine samples

Indole or indazole-based synthetic cannabinoids (SCs) bearing substituents derived from valine or tert-leucine are frequently abused new psychoactive substances (NPS). The emergence of 5F-MDMB-PICA (methyl N-{[1-(5-fluoropentyl)-1H-indol-3-yl]carbonyl}-3-methylvalinate) on the German drug market is a further example of a substance synthesized in the context of scientific research being misused by clandestine laboratories by adding it to 'legal high' products. In this work, we present the detection of 5F-MDMB-PICA in several legal high products by gas chromatography-mass spectrometry (GC-MS) analysis. To detect characteristic metabolites suitable for a proof of 5F-MDMB-PICA consumption by urine analysis, pooled human liver microsome (pHLM) assays were performed and evaluated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS) techniques to generate reference spectra of the in vitro phase I metabolites. The in vivo phase I metabolism was investigated by the analysis of more than 20 authentic human urine specimens and compared to the data received from the pHLM assay. Biotransformation of the 5-fluoropentyl side chain and hydrolysis of the terminal methyl ester bond are main phase I biotransformation steps. Two of the identified main metabolites formed by methyl ester hydrolysis or mono-hydroxylation at the indole ring system were evaluated as suitable urinary biomarkers and discussed regarding the interpretation of analytical findings. Exemplary analysis of one urine sample for 5F-MDMB-PICA phase II metabolites showed that two of the main phase I metabolites are subject to extensive glucuronidation prior to renal excretion. Therefore, conjugate cleavage is reasonable for enhancing sensitivity. Commercially available immunochemical pre-tests for urine proved to be unsuitable for the detection of 5F-MDMB-PICA consumption. Copyright © 2017 John Wiley & Sons, Ltd.

A useful ring transformation route to novel thiazepino[7,6-b]indoles from monochloro-β-lactam-fused 1,3-thiazino[6,5-b]indoles, analogues of cyclobrassinin

The Staudinger ketene-imine cycloaddition reactions of cyclobrassinin phytoalexin analogues 2-aryl-4,9-dihydro-1,3-thiazino[6,5-b]indoles with chloroacetyl chloride as a ketene source were investigated under different conditions. Both β-lactam ring formation and the N-chloroacetylation of the indole moiety took place. The indole N-chloroacetyl group can be easily removed by treatment in the presence of silica gel in methanol at reflux temperature. The selective β-lactam formation can be also achieved in certain cases under milder Staudinger conditions. The treatment of azeto[2,1-b]thiazino[6,5-b]indole-1-one derivatives with sodium ethoxide in ethanol provided the novel thiazepino[7,6-b]indole ring systems in a one-step ring transformation. The structures of the new ring systems were determined by means of IR and NMR spectroscopy.

N-[(3-Bromo-1-phenylsulfonyl-1H-indol-2-yl)methyl]-4-fluoroaniline

In the title compound, C21H16BrFN2O2S, the indole ring system makes dihedral angles of 87.23 (10) and 77.58 (9)° with the fluorobenzene and phenyl rings, respectively. The molecular structure is stabilized by a C—H...O and a C—H...Br intramolecular hydrogen bond, which generateS(6) andS(8) ring motifs, respectively. In the crystal, molecules are linked by C—H...π interactions, forming ribbons propagating along thea-axis direction. Within the ribbons, there are offset π–π interactions present involving inversion-related molecules [intercentroid distance = 3.650 (1) Å].

3-(1H-Indol-3-yl)-2-benzofuran-1(3H)-one

In the title compound, C16H11NO2, the benzofuran and indole ring systems are nearly orthogonal, subtending a dihedral angle of 86.55 (4)°. The crystal structure features an N—H...O hydrogen bond, which leads to the formation of chains propagating along the a-axis direction.

Synthesis and structure of 1-(2-bromo-phen-yl)-2-chloro-3-(2-chloracet-yl)-1H-indole.

In the title indole derivative, C16H10BrCl2NO, the dihedral angle between the mean plane of the indole ring system and the mean plane of the disordered 2-bromo-phenyl ring is 77.6 (1)°. The non-H atoms of the chloracetyl group are essentially coplanar with the indole core. In the crystal, pairs of mol-ecules are face-to-face embraced via two weak C-H⋯O hydrogen bonds, forming inversion dimers with an inter-planar distance between two parallel indole planes of 3.360 (3) Å. These dimers are connected by head-to-head Cl⋯Cl inter-molecular contacts to build a two-dimensional mol-ecular sheet parallel to (101). Neighbouring mol-ecular sheets are stacked together to construct the three-dimensional structure by further short Cl⋯Cl inter-molecular contacts. The atoms of the bromo-phenyl group were refined as disordered over two sets of sites with refined occupancies of 0.61 (2) and 0.39 (2).

Exploring structural requirements of unconventional Knoevenagel-type indole derivatives as anticancer agents through comparative QSAR modeling approaches

An indole ring system is considered as a versatile scaffold in the pharmaceutical field. In this article, comparative QSAR modeling (2D-QSAR, 3D-QSAR; kNN-MFA and CoMSIA) was performed on some Knoevenagel-type cytotoxic indole derivatives to understand the structural requirements for the cytotoxic property of these compounds. The 2D-QSAR model was statistically significant and imparted high predictive ability (nTrain = 30; R = 0.917; [Formula: see text] = 0.801; [Formula: see text] = 0.757; Q2 = 0.722; nTest = 9; [Formula: see text] = 0.799). A statistically significant 3D-QSAR kNN-MFA model (both with stepwise forward and simulated annealing model selection method) as well as a 3D-QSAR CoMSIA model was developed to identify the key chemical features associated with enhancing the cytotoxic activities of these indoles. The results suggest that the presence of bulky group in R position can cause better cytotoxic activities. Consequently, substitution with cyano group at X portion and cyano/ester/keto/sulphonyl features at Y position is favourable for the cytotoxicity. However, hydrophobic features in R′ region are unfavourable for the biological activity. The chemical and structural features identified from the study may provide important avenues to modulate the structure of these indoles to a desirable biological end point.

Indole Molecules as Inhibitors of Tubulin Polymerization: Potential New Anticancer Agents, an Update (2013–2015)

Discovery of new indole-based tubulin polymerization inhibitors will continue to dominate the synthetic efforts of many medicinal chemists working in the field. The indole ring system is an essential part of several tubulin inhibitors identified in the recent years. The present review article will update the synthesis, anticancer and tubulin inhibition activities of several important new indole classes such as 2-phenylindoles (28, 29 & 30), oxindoles (35 & 38), indole-3-acrylamides (44), indolines (46), aroylindoles (49), carbozoles (75, 76 & 82), azacarbolines (87) and annulated indoles (100-105).

1-Benzyl-5-chloroindoline-2,3-dione

The title compound, C15H10ClNO2, crystallizes with two molecules (AandB) in the asymmetric unit, which have almost identical conformations (r.m.s. overlay fit = 0.057 Å). In moleculeA, the dihedral angle between the indole ring system (r.m.s. deviation = 0.025 Å) and the phenyl group is 71.39 (8)°. Equivalent data for moleculeBare 0.023 Å and 71.43 (9)°. In the crystal, theAandBmolecules are linked by a C—H...O hydrogen bond and aromatic π–π stacking is also observed [shortest centroid–centroid separation = 3.5810 (11) Å].

2-[(2-Fluorophenyl)(1H-indol-3-yl)methyl]-1H-indole

In the title compound, C23H17FN2, the indole ring systems are oriented orthogonally, as indicated by the dihedral angle between them of 88.49 (5)°. The fluorophenyl ring is nearly perpendicular to one of the indole ring systems [dihedral angle = 85.31 (16)°] and twisted by 63.6 (6)° from the other. In the crystal, N—H...π, C—H...π and C—H...F interactions occur, forming a three-dimensional network.

5-Benzoyl-2-(5-bromo-1H-indol-3-yl)-4-(4-methoxyphenyl)-1H-pyrrole-3-carbonitrile

In the title compound, C27H18BrN3O, the indole and central pyrrole ring systems are inclined to one another by 13.15 (15)°. The carbonitrile group is almost coplanar with its attached pyrrole ring, the C[triple-bond]N bond making a dihedral angle of 1.9 (2)° with the ring plane. The 4-methoxybenzene ring and the benzoyl ring are inclined to the central pyrrole ring by 55.1 (2) and 51.5 (2)°, respectively. The dihedral angle between these two benzene rings is 37.68 (17)°. In the crystal, molecules are linked by pairs of N—H...N hydrogen bonds, forming inversion dimers with anR22(16) ring motif. The dimers are linked by offset π–π interactions [intercentroid distance = 3.614 (2) Å], which leads to the formation of chains propagating in the [010] direction.

5-Benzoyl-2-(5-bromo-1H-indol-3-yl)-4-(4-nitrophenyl)-1H-pyrrole-3-carbonitrile dimethyl sulfoxide monosolvate

The title compound, C26H15BrN4O3·C2H6OS, contains five rings. The indole unit is essentially planar [maximum deviation = 0.0067 (1) Å for the N atom]. The central pyrrole ring makes dihedral angles of 44.1 (2) and 51.3 (2)° with the pendant indole ring system and the nitrobenzene ring, respectively. The benzene ring is inclined with the central pyrrole ring by 51.9 (3)°. In the crystal, N—H...O hydrogen-bonding interactions between aromatic-H-atom donors and sulfoxide-O-atom acceptors result in the formation of inversion dimers with anR42(16) ring motif. The molecules are further linked into chains running along thecaxis by N—H...O, C—H...O and C—H...N hydrogen bonds.

5-(2-Hydroxybenzoyl)-2-(1H-indol-3-yl)pyridine-3-carbonitrile

In the title compound, C21H13N3O2, the indole and pyridine rings are planar. The pyridine ring is in an antiperiplanar (−ap) orientation with the indole ring system and an antiperiplanar (+ap) orientation with the hydroxyphenyl ring. An intramolecular O—H...O hydrogen bond stabilizes the molecular structure. In the crystal, N—H...N hydrogen bonds involving the indole NH group and the cyanide nitrogen atom lead to the formation of a two-dimensional supramolecular network lying parallel to (011).

Crystal structures of four indole derivatives with a phenyl substituent at the 2-position and a carbonyl group at the 3-position: the C(6) N-H⋯O chain remains the same, but the weak reinforcing inter-actions are different.

We describe the crystal structures of four indole derivatives with a phenyl ring at the 2-position and different carbonyl-linked substituents at the 3-position, namely 1-(2-phenyl-1H-indol-3-yl)ethanone, C16H13NO, (I), 2-cyclo-hexyl-1-(2-phenyl-1H-indol-3-yl)ethanone, C22H23NO, (II), 3,3-dimethyl-1-(2-phenyl-1H-indol-3-yl)butan-1-one, C20H21NO, (III), and 3-benzoyl-2-phenyl-1H-indole, C21H15NO, (IV). In each case, the carbonyl-group O atom lies close to the indole-ring plane and points towards the benzene ring. The dihedral angles between the indole ring system and 2-phenyl ring for these structures are clustered in a narrow range around 65°. The dominant inter-molecular inter-action in each case is an N-H⋯O hydrogen bond, which generates a C(6) chain, although each structure possesses a different crystal symmetry. The C(6) chains are consolidated by different (C-H⋯O, C-H⋯π and π-π stacking) weak inter-actions, with little consistency between the structures.

1-[(4-Methoxyphenyl)sulfonyl]-1H-indole-3-carbaldehyde

In the molecule of the title compound, C16H13NO4S, the mean plane of the indole ring system and that of the methoxyphenyl ring, which are bridged by a sulfonyl group, are inclined at a dihedral angle of 88.98 (9)°. The crystal structure is stabilized by intermolecular C—H...O hydrogen bonds.

Crystal structure of (E)-diethyl 2-[(1-phenyl-sulfonyl-1H-indol-3-yl)methyl-idene]succinate.

In the title compound, C23H23NO6S, the phenyl ring is perpendicular [dihedral angle = 89.34 (9)°] to the indole ring system. In the mol­ecule, the eth­oxy groups are each disordered over two sets of sites with occupancy ratios of 0.671 (6):0.329 (6) and 0.75 (3):0.25 (3). The mol­ecular conformation is consolidated by a weak C—H⋯O interaction, which generates an S(6) graph–set motif. The packing of the mol­ecules in the crystal structure features weak C—H⋯π inter­actions.

Crystal structure of 2-[2-phenyl-1-(phenyl-sulfon-yl)eth-yl]-1-phenyl-sulfonyl-1H-indole.

In the title compound, C28H23NO4S2, the indole ring system (r.m.s. deviation = 0.007 Å) subtends dihedral angles of 78.69 (13) and 38.97 (13)° with the planes of the N- and C-bonded sulfonyl­benzene rings, respectively, and these two benzene rings are inclined to each other at an angle of 65.45 (16)°. The methyl­ene-linked phenyl ring is twisted at an angle of 81.80 (13)° from the indole ring. The mol­ecular structure features two short intra­molecular C—H⋯O contacts, which both generate S(6) rings. In the crystal, mol­ecules are linked by C—H⋯O hydrogen bonds and C—H⋯π inter­actions, generating a three-dimensional network.

Crystal structure of 3-(2-nitro-phen-yl)-1-(1-phenyl-sulfonyl-1H-indol-3-yl)propan-1-one.

In the title compound, C23H18N2O5S, the phenyl and benzene rings subtend dihedral angles of 78.18 (10) and 30.18 (9)°, respectively, with the indole ring system (r.m.s. deviation = 0.022 Å). The crystal structure features weak C—H⋯O and C—H⋯π inter­actions, which link the mol­ecules into a three-dimensional network.

Crystal structure of 5-(5-chloro-2-hydroxy-benzo-yl)-2-(2-methyl-1H-indol-3-yl)nicotino-nitrile.

In the title compound, C22H14ClN3O2, the indole unit is essentially coplanar, with a maximum deviation of 0.035 Å for the C atom bearing the methyl group. The central pyridine ring is inclined to the indole ring system by 43.7 (1)°. The dihedral angle between the phenyl ring and the indole ring system is 15.7 (2)°, while that between the phenyl ring and the central pyridine ring is 46.3 (1)°. The mol­ecular structure is stabilized by an intra­molecular O—H⋯O hydrogen bonding, forming an S(6) ring motif. In the crystal, mol­ecules are linked via pairs of N—H⋯N hydrogen bonds, forming inversion dimers with an R 2 2(16) ring motif. The crystal structure also features C—H⋯π and π–π inter­actions [centroid–centroid separation = 3.688 (1) Å].

Crystal structure of N-{[3-bromo-1-(phenyl-sulfon-yl)-1H-indol-2-yl]meth-yl}benzene-sulfonamide.

In the title compound, C21H17BrN2O4S2, the indole ring system subtends dihedral angles of 85.96 (13) and 9.62 (16)° with the planes of the N- and C-bonded benzene rings, respectively. The dihedral angles between the benzene rings is 88.05 (17)°. The mol­ecular conformation is stabilized by intra­molecular N—H⋯O and C—H⋯O hydrogen bonds and an aromatic π–π stacking [centroid-to-centroid distance = 3.503 (2) Å] inter­action. In the crystal, short Br⋯O [2.9888 (18) Å] contacts link the mol­ecules into [010] chains. The chains are cross-linked by weak C—H⋯π inter­actions, forming a three-dimensional network.

Crystal structure of (E)-2-(4-meth-oxy-styr-yl)-3-methyl-1-phenyl-sulfonyl-1H-indole.

In the title compound, C24H21NO3S, the dihedral angles between the indole ring system (r.m.s. deviation = 0.030 Å) and the sulfur and ethyl­ene-bonded benzene rings are 80.2 (2) and 49.29 (15)°, respectively. The dihedral angle between the pendant benzene rings is 37.7 (2)°. In the crystal, mol­ecules are linked by C—H⋯O hydrogen bonds and weak C—H⋯π and π–π [centroid-to-centroid distances = 3.549 (2) and 3.743 (3) Å] inter­actions, forming a three-dimensional network.