Indole Ring System Research Articles

The crystal structures determination and Hirshfeld surface analysis of N-(4-bromo-3-methoxyphenyl)- and N-{[3-bromo-1-(phenylsulfonyl)-1H-indol-2-yl]methyl}- derivatives of N-{[3-bromo-1-(phenylsulfonyl)-1H-indol-2-yl]methyl}benzenesulfonamide

Two new phenylsulfonylindole derivatives, namely, N-{[3-bromo-1-(phenylsulfonyl)-1H-indol-2-yl]methyl}-N-(4-bromo-3-methoxyphenyl)benzenesulfonamide, C28H22Br2N2O5S2, (I), and N,N-bis{[3-bromo-1-(phenylsulfonyl)-1H-indol-2-yl]methyl}benzenesulfonamide, C36H27Br2N3O6S3, (II), reveal the impact of intramolecular π–π interactions of the indole moieties as a factor not only governing the conformation of N,N-bis(1H-indol-2-yl)methyl)amines, but also significantly influencing the crystal patterns. For I, the crystal packing is dominated by C—H...π and π–π bonding, with a particular significance of mutual indole–indole interactions. In the case of II, the molecules adopt short intramolecular π–π interactions between two nearly parallel indole ring systems [with the centroids of their pyrrole rings separated by 3.267 (2) Å] accompanied by a set of forced Br...O contacts. This provides suppression of similar interactions between the molecules, while the importance of weak C—H...O hydrogen bonding to the packing naturally increases. Short contacts of the latter type [C...O = 3.389 (6) Å] assemble pairs of molecules into centrosymmetric dimers with a cyclic R 2 2(13) ring motif. These findings are consistent with the results of a Hirshfeld surface analysis and together they suggest a tool for modulating the supramolecular behavior of phenylsulfonylated indoles.

Synthesis of 3‐CF3‐Indoles from HFO‐1234ze(E) via Cross‐Coupling and Intramolecular Cyclization

AbstractThe synthesis of indoles with a trifluoromethyl group has attracted a lot of attention because they are promising structural subunits for pharmaceuticals and agrochemicals. As part of our project aimed toward the upcycling of hydrofluoroolefins (HFOs), we developed a method to construct a CF3‐bearing indole ring system through the Suzuki–Miyaura cross‐coupling of a brominated HFO‐1234ze(E) (CF3CH=CHF) with N‐tosylated o‐borylanilines, followed by nucleophilic 5‐endo‐trig cyclization at the vinylic position of the generated fluorostyrenes. We found that the Pd2(dba)3/SPhos catalyst system in the presence of K2CO3 and water in toluene afforded the corresponding 3‐CF3‐indoles in high yields in a one‐pot operation.

Crystal structure determination and Hirshfeld surface analysis of N-acetyl-N-3-meth-oxy-phenyl and N-(2,5-di-meth-oxy-phen-yl)-N-phenyl-sulfonyl derivatives of N-[1-(phenyl-sulfon-yl)-1H-indol-2-yl]methanamine.

Two new [1-(phenyl-sulfon-yl)-1H-indol-2-yl]methanamine derivatives, namely, N-(3-meth-oxy-phen-yl)-N-{[1-(phenyl-sulfon-yl)-1H-indol-2-yl]meth-yl}acetamide, C24H22N2O4S, (I), and N-(2,5-di-meth-oxy-phen-yl)-N-{[1-(phenyl-sulfon-yl)-1H-indol-2-yl]meth-yl}benzene-sulfonamide, C29H26N2O6S2, (II), reveal a nearly orthogonal orientation of their indole ring systems and sulfonyl-bound phenyl rings. The sulfonyl moieties adopt the anti-periplanar conformation. For both compounds, the crystal packing is dominated by C-H⋯O bonding [C⋯O = 3.312 (4)-3.788 (8) Å], with the structure of II exhibiting a larger number, but weaker bonds of this type. Slipped π-π inter-actions of anti-parallel indole systems are specific for I, whereas the structure of II delivers two kinds of C-H⋯π inter-actions at both axial sides of the indole moiety. These findings agree with the results of Hirshfeld surface analysis. The primary contributions to the surface areas are associated with the contacts involving H atoms. Although II manifests a larger fraction of the O⋯H/H⋯O contacts (25.8 versus 22.4%), most of them are relatively distal and agree with the corresponding van der Waals separations.

The crystal structures and Hirshfeld surface analysis of three new bromo-substituted 3-methyl-1-(phenylsulfonyl)-1H-indole derivatives

Three new 1H-indole derivatives, namely, 2-(bromomethyl)-3-methyl-1-(phenylsulfonyl)-1H-indole, C16H14BrNO2S, (I), 2-[(E)-2-(2-bromo-5-methoxyphenyl)ethenyl]-3-methyl-1-(phenylsulfonyl)-1H-indole, C24H20BrNO3S, (II), and 2-[(E)-2-(2-bromophenyl)ethenyl]-3-methyl-1-(phenylsulfonyl)-1H-indole, C23H18BrNO2S, (III), exhibit nearly orthogonal orientations of their indole ring systems and sulfonyl-bound phenyl rings. Such conformations are favourable for intermolecular bonding involving sets of slipped π–π interactions between the indole systems and mutual C—H...π hydrogen bonds, with the generation of two-dimensional monoperiodic patterns. The latter are found in all three structures, in the form of supramolecular columns with every pair of successive molecules related by inversion. The crystal packing of the compounds is additionally stabilized by weaker slipped π–π interactions between the outer phenyl rings (in II and III) and by weak C—H...O, C—H...Br and C—H...π hydrogen bonds. The structural significance of the different kinds of interactions agree with the results of a Hirshfeld surface analysis and the calculated interaction energies. In particular, the largest interaction energies (up to −60.8 kJ mol−1) are associated with pairing of antiparallel indole systems, while the energetics of weak hydrogen bonds and phenyl π–π interactions are comparable and account for 13–34 kJ mol−1.

Chemo-Enzymatic Synthesis of Bioactive Carbazole Derivatives

Carbazoles are key scaffolds of either antimicrobial/antiviral alkaloid natural products or therapeutics. As such, access to structurally diverse indole-containing carbazoles has attracted considerable attention. In this report, a pilot study is described using biotransformation to provide carbazoles that contain various acyl substituents. The biotransformation system contains the thiamine-diphosphate (ThDP)-dependent enzyme NzsH, the FabH-like 3-ketoacyl-ACP synthase NzsJ, and the aromatase/cyclase NzsI, encoded in the biosynthetic gene cluster (nzs) of the bacterial carbazole alkaloid natural product named neocarazostatin A. The utilization of a range of acyl-SNACs (synthetic acyl-thioester analogues of the native substrate) together with indole-3-pyruvate and pyruvate in the designed biotransformation system allows production of carbazole derivatives. Our results demonstrate that this three-enzyme system displays a considerable substrate profile toward acyl donors for production of carbazoles with different acyl substituents. Finally, two more enzymes were included in the biotransformation system: the tryptophan synthase stand-alone β-subunit variant, PfTrpB, generated from directed evolution in the literature, and a commercially available L-amino acid oxidase (LAAO). The addition of these two enzymes allows the transformation to start with indole building blocks to provide carbazoles with modifications in the indole ring system.

(2,4-Di-chloro-benzyl-idene)[2-(1H-indol-3-yl)eth-yl]amine.

In the title compound, C17H14Cl2N2, the mol-ecule exists in an E configuration with respect to the C=N bond of the Schiff base fragment. The dihedral angle between the indole ring system and the benzene ring is 80.86 (12)°. In the crystal, mol-ecules are connected by N-H⋯N hydrogen bonds, generating a C(7) chain extending along the a-axis direction. No aromatic π-π stacking occurs but weak C-H⋯π inter-actions are observed.

Crystal structure and Hirshfeld surface analysis of 3-(bromo-meth-yl)-2-[1,2-di-bromo-2-(6-nitro-benzo[d][1,3]dioxol-5-yl)eth-yl]-1-(phenyl-sulfon-yl)-1H-indole chloro-form 0.585-solvate.

The title indole derivative, C24H17Br3N2O6S, crystallizes with a partial occupancy [0.585 (4)] CHCl3 solvent mol-ecule. The dihedral angles between the indole ring system and pendant nitro-benzodioxolane rings system and phenyl-sulfonyl ring are 4.81 (14) and 72.24 (19)°, respectively. In the crystal, the indole mol-ecules are linked to each other and to the chloro-form mol-ecule by weak C-H⋯O, C-H⋯Cl, C-H⋯π, C-Br⋯π and C-Cl⋯π and aromatic π-π stacking inter-actions. A Hirshfeld surface analysis was carried out and the inter-molecular contacts with the most significant contributions are H⋯O/O⋯H (24.3%), H⋯H (18.4%), Br⋯H/H⋯Br (16.8%) and C⋯H/H⋯C (8.4%).

Chemoenzymatic Synthesis of Indole-Containing Acyloin Derivatives.

Indole-containing acyloins are either key intermediates of many antimicrobial/antiviral natural products or building blocks in the synthesis of biologically active molecules. As such, access to structurally diverse indole-containing acyloins has attracted considerable attention. In this report, we present a pilot study of using biotransformation to provide acyloins that contain various indole substituents. The biotransformation system contains the tryptophan synthase standalone β-subunit variant, PfTrpB6, generated from directed evolution in the literature; a commercially available L-amino acid oxidase (LAAO); and the thiamine-diphosphate (ThDP)-dependent enzyme NzsH, encoded in the biosynthetic gene cluster (nzs) of the bacterial carbazole alkaloid natural product named neocarazostatin A. The utilization of the first two enzymes, the PfTrpB variant and LAAO, is designed to provide structurally diverse indole 3-pyruvate derivatives as donor substrates for NzsH-catalysed biotransformation to provide acyloin derivatives. Our results demonstrate that NzsH displays a considerable substrate profile toward donor substrates for production of acyloins with different indole ring systems, suggesting that NzsH could be further explored as a potential biocatalyst via directed evolution to improve the catalytic efficiency in the future.

Synthesis and anticancer screening of some novel Pd-catalysed 3-methyl indole based analogues on Mia PaCa-2 cell line

Indole is a most prerogative moiety in the evaluation of anticancer agents for its versatility and bio-diversity. The indole based compounds have been reported by the researchers in the last decade with potent anticancer activities. The coupled indole ring system with other biodynamic moieties is known to increase the bio-efficiency. Hence, a series of 3-methyl-indole-2-pyrindine coupled secondary amines have been synthesized via Suzuki-Miyaura and Buchwald Hartwig coupling. The compounds 9a-e have been docked against Hypoxia-inducible factor 1α (HIF-1α) enzyme to demonstrate the binding interactions with the active site, shown the binding affinity from -7.5 to -8.1 Kcal/mol and disclosed the potentiality of synthesized compounds to bind and inhibits the HIF-1α (Pdb Id: 3KCX) pathway and predicted several in silico ADMET descriptors for the 3-methyl Indole analogues. The molecules were screened for their anti-pancreatic cancer activity and tested against Mia PaCa-2 cell line by MTT assay, revealed that; compound 9d exhibited a greater antiproliferation activity in the series, with IC50 of 73.63±2.05 µM. Our present findings revealed that 9d might be a pursuable lead for further anti-pancreatic cancer studies.

1-(Phenyl-sulfon-yl)-1H-indole-2-carbaldehyde.

The title compound, C15H11NO3S, was prepared by a facile synthetic approach. The N atom in the pyrrole ring of the indole moiety is pyramidal (bond-angle sum = 350.0°) and the phenyl ring of the phenyl-sulfonyl motif forms a dihedral angle of 76.24 (7)° with the mean plane of the indole ring system. In the crystal, C-H⋯O and C-H⋯π inter-actions link the mol-ecules into a three-dimensional network.

Investigation of solid state architectures in tetrazolyl tryptophol stabilized by crucial aromatic interactions and hydrogen bonding: Experimental and theoretical analysis

The present study reports the synthesis of a new nitrogen rich hybrid compound namely tetrazolyl tryptophol 6 achieved through a multistep synthetic approach. The structure of the target tetrazole-indole hybrid was established using FTIR, 1H- and 13C NMR, HRMS, and X-ray diffraction data. Investigation of solid state architectures in tetrazolyl tryptophol revealed that an intramolecular N5-H5N…N4 hydrogen bond links the 5-membered ring of the indole to the tetrazole ring. O1-H1O…N3 and N1-H1N…O1 hydrogen bonds and π…π contacts also emerged as crucial contributors in the formation of supramolecular topology of tetrazole-indole hybrid. Numerous centroid to centroid contacts involving the aromatic rings of both the indole ring system and the tetrazole ring link adjacent molecules in an obverse face-to-face fashion. Hirshfeld surface analysis further revealed the prevailing significance of π…π and H-bonding contacts. The mechanical stability of the crystal packing through crystal voids analysis and intermolecular interaction energies were also calculated. Finally, DFT calculations were performed to evaluate the hydrogen bonding and π…π stacking contacts with their rationalization and characterization using MEP surfaces, QTAIM and NCIPlot analysis.

Crystal structure of N-(1H-indol-2-yl-methyl-idene)-4-meth-oxy-aniline.

The mol-ecule of the title compound, C16H14N2O, contains an essentially planar indole ring system and a phenyl ring. In the crystal, the mol-ecules are linked by a weak inter-molecular C-H⋯O hydrogen bond and C-H⋯π inter-actions, forming a one-dimensional column structure along the b-axis direction. These columns are linked by other C-H⋯π inter-actions, forming a two-dimensional network structure.

Enantioselective Total Synthesis of (+)‐Nordasycarpidone, (+)‐Dasycarpidone, and (+)‐Uleine

AbstractThe structure of uleine type alkaloids is characterized by the presence of a bridged tetracyclic hexahydro‐1H‐1,5‐methanoazocino[4,3‐b]indole ring system 1. Various strategies have been developed to access this polycyclic structural motif. We report herein a one‐step conversion of appropriately functionalized 1,3,4‐trisubstituted cyclopent‐1‐ene to 1 by way of an integrated oxidation/reduction/cyclization (iORC) process. This domino sequence, initiated by oxidative cleavage of cyclopentene ring, generated subsequently a cyclohexenone, an indole and a 1,3‐bridged piperidine ring through formation of one C−C and two C−N bonds. Compound 1 is subsequently converted to nordasycarpidone, dasycarpidone and uleine. The chirality of the molecule was introduced by enzymatic desymmetrization of commercially available meso cis‐3,5‐diacetoxy‐1‐cyclopentene.

Naturally Available Nitrogen-Containing Fused Heterocyclics as Prospective Lead Molecules in Medicinal Chemistry

Heterocyclic compounds constitute one of the largest and most versatile families of organic compounds. There are many heterocyclic compounds that are being isolated from natural sources and day by day the number is increasing rapidly due to their enormous utility. Nitrogen containing heterocyclic compounds have a prominent role in medicinal chemistry, biochemistry and other streams of science. In this review, we have covered most of the biologically active nitrogen containing heterocyclic compounds obtained from the natural sources including indole, carbazole, quinoline, isoquinoline and benzothiazole ring system. These isolated nitrogen containing heterocyclic compounds render wide spectrum of biological activities including antifungal, anti-inflammatory, antibacterial, antioxidants, anticonvulsant, anti-allergic, herbicidal and anticancer activities.

Dimethyl 3,3'-[(4-nitro-phen-yl)methyl-ene]bis-(1H-indole-2-carboxyl-ate) ethanol hemisolvate.

There are two main molecules in asymmetric unit of the title compound, C27H21N3O6·0.5C2H5OH. In both, the indole ring systems are approximately perpendicular to each other, at dihedral angles of 69.3 (5) and 82.8(4)°. In the crystal, mol-ecules are linked by N-H⋯O and O-H⋯O hydrogen bonds into a three-dimensional supra-molecular architecture. The solvent ethanol mol-ecule acts as a donor, forming an O-H⋯O hydrogen bond, reinforcing the structure.

Biomimetically Inspired, One-Step Synthesis of Exotine A and Exotine B.

The one-step syntheses of exotine A and exotine B, which comprise the unusual coumarin-cyclohepta[b]indole ring system, have been achieved via the biomimetically inspired combination of indole, prenal, and either trans-dehydroosthol or gleinadiene. This facile three-component reaction delivered a mixture (17:1) of exotine A and 11'-epi-exotine A in a 43% yield from trans-dehydroosthol and a mixture (4:1) of exotine B and 11'-epi-exotine B in a 50% yield from gleinadiene. Some mechanistic aspects of this process were explored, and spectral evidence for 3,3'-spiroindolenine intermediates was obtained. Moreover, a skeletal isomer of exotine A that likely originates from a 1,2-alkyl rearrangement of a protonated 3,3'-spiroindolenine was isolated and characterized by X-ray crystallography. These findings not only provide experimental support for Jiang's proposed biosynthesis of exotine A and exotine B but also foreshadow the existence of other exotine-derived natural products having isomeric frameworks. Exploratory attempts to induce an enantioselective 3CR using a chiral phosphoric acid were unsuccessful.

Diethyl 3,3'-[(3-fluoro-phen-yl)methyl-ene]bis-(1H-indole-2-carboxyl-ate).

In the title compound, C29H25FN2O4, the mean planes of the indole ring systems are approximately perpendicular to one another [dihedral angle = 88.3 (4)°]. The benzene ring is twisted with respect to the indole ring systems by 49.8 (5) and 77.6 (3)°. In the crystal, pairs of N-H⋯O hydrogen bonds link the mol-ecules into the inversion dimers which are further linked into supra-molecular chains propagating along the [110] direction.

Tryptamine derivatives disarm colistin resistance in polymyxin-resistant gram-negative bacteria.

The last three decades have seen a dwindling number of novel antibiotic classes approved for clinical use and a concurrent increase in levels of antibiotic resistance, necessitating alternative methods to combat the rise of multi-drug resistant bacteria. A promising strategy employs antibiotic adjuvants, non-toxic molecules that disarm antibiotic resistance. When co-dosed with antibiotics, these compounds restore antibiotic efficacy in drug-resistant strains. Herein we identify derivatives of tryptamine, a ubiquitous biochemical scaffold containing an indole ring system, capable of disarming colistin resistance in the Gram-negative bacterial pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli while having no inherent bacterial toxicity. Resistance was overcome in strains carrying endogenous chromosomally-encoded colistin resistance machinery, as well as resistance conferred by the mobile colistin resistance-1 (mcr-1) plasmid-borne gene. These compounds restore a colistin minimum inhibitory concentration (MIC) below the Clinical & Laboratory Sciences Institute (CLSI) breakpoint in all resistant strains.

Diethyl 3,3′-[(4-fluorophenyl)methylidene]bis(1H-indole-2-carboxylate)

In the title compound, C29H25FN2O4, the mean planes of the indole ring systems (r.m.s. deviations = 0.0107 and 0.0158 Å) are approximately perpendicular to each other, subtending a dihedral angle of 87.43 (16)°. The 4-fluorophenyl ring is twisted by 77.6 (2) and 83.0 (2)° with respect to the two indole ring systems. In the crystal, molecules are linked by N—H...O hydrogen bonds, forming layers parallel to the (001) plane. The layers are linked by C—H...π interactions, forming a supramolecular three-dimensional network.

Crystal structures of 6a,6b,7,11a-tetra-hydro-6H,9H-spiro-[chromeno[3',4':3,4]pyrrolo-[1,2-c]thia-zole-11,3'-indoline]-2',6-dione and 5'-methyl-6a,6b,7,11a-tetra-hydro-6H,9H-spiro-[chromeno[3',4':3,4]pyrrolo-[1,2-c]thia-zole-11,3'-indoline]-2',6-dione.

The title compounds, C20H16N2O3S, (I), and C21H18N2O3S, (II), differ by the presence of a methyl group in position 5 on the 1H-indole-2-one ring of compound (II). The two compounds have a structural overlap r.m.s. deviation of 0.48 Å. There is a significant difference in the conformation of the thia-zolidine ring: it has a twisted conformation on the fused N-C bond in (I), but an envelope conformation in compound (II) with the S atom as the flap. The planar pyrrolidine ring of the indole ring system is normal to the mean plane of the five-membered pyrrolidine ring of the pyrrolo-thia-zole unit in both compounds, with dihedral angles of 88.71 (9) and 84.59 (8)°. The pyran rings in both structures have envelope conformations with the methyl-ene C atom adjacent to the C=O group as the flap. In both compounds, there is a short intra-molecular C-H⋯O contact present. In the crystal of (I), mol-ecules are linked by C-H⋯O hydrogen bonds forming chains propagating along the b-axis direction. The chains are linked by N-H⋯π inter-actions, forming layers parallel to (10). In the crystal of (II), mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers which are linked by C-H⋯O hydrogen bonds to form a three-dimensional structure.