Unsubstituted Indole Research Articles

Divergent Electrochemical Synthesis of Indoles through pKa Regulation of Amides: Synthetic and Mechanistic Insights.

A divergent synthetic approach to access highly substituted indole scaffolds is illustrated. By virtue of a tunable electrochemical strategy, distinct control over the C-3 substitution pattern was achieved by employing two analogous 2-styrylaniline precursors. The chemoselectivity is governed by the fine-tuning of the acidity of the amide proton, relying on the appropriate selection of N-protecting groups, and assisted by the reactivity of the electrogenerated intermediates. Detailed mechanistic investigations based on cyclic voltametric experiments and computational studies revealed the crucial role of water additive, which assists the proton-coupled electron transfer event for highly acidic amide precursors, followed by an energetically favorable intramolecular C-N coupling, causing exclusive fabrication of the C-3 unsubstituted indoles. Alternatively, the implementation of an electrogenerated cationic olefin activator delivers the C-3 substituted indoles through the preferential nucleophilic nature of the N-acyl amides. This electrochemical approach of judicious selection of N-protecting groups to regulate pKa/E° provides an expansion in the domain of switchable generation of heterocyclic derivatives in a sustainable fashion, with high regio- and chemoselectivity.

A macrocycle-based new organometallic nano-vessel towards sustainable C2-selective arylation of free indole in water.

C2-selectivity of unsubstituted indole over facile C3-substitution is attempted by utilizing the π-cavity of a nano-vessel made up of a palladium complex of an amino-ether heteroditopic macrocycle. Functional group tolerance (cyano, nitro, halo, ester, etc.), a broad substrate scope and outstanding selectivities with excellent yields (80-93%) of the desired products have been achieved in 12 h by maintaining all sustainable conditions like aqueous medium, recyclable catalyst, one-pot reaction, no external additives, mild temperature, etc. Interestingly, we observed that electron-deficient indole derivatives underwent the present transformation with marginally superior reactivity in comparison with electron-rich indole derivatives. This approach establishes a green pathway for selective C-C coupling employing a π-cavitand as a nano-reactor.

Substituent effects on indole universal bases in DNA

A series of eleven 5-substituted-indole nucleoside residues were synthesized and incorporated into 15-mer oligodeoxynucleotide duplexes with each of the four natural bases (A, G, C, T) paired with the non-natural residues. The universal base properties of these residues were evaluated by comparing the stabilities of these complexes determined by UV thermal denaturation experiments. All of the substituted indoles were more stable than an unsubstituted indole residue, and measures of electronic influences of substituents on the indole pi system correlate with stability. Several residues were more promiscuous than the previously studied 5-nitroindole residue, but the relationship between substituents and selectivity is not clear.

Red-sea dolomite as a sustainable catalyst in the synthesis of bis-indolyl methanes with molecular docking validation as HIV-1 replication inhibitor

ABSTRACT. Dolomite minerals were collected from the Red Sea Mountains around the Sokhna region. The rock was collected, rinsed, and crushed using a ball mailing machine and used without further purification. The dolomite sample was characterized using FTIR, XRD, SEM/EDAX, and mapping to ensure their composition and homogeneity. The obtained data reveal that the presence of a homogenous crystalline structure of CaMg(CO3)2. The characterized rock was used as a catalyst in the eco-friendly synthesis of bis-indolyl methane derivatives by reacting two moles of unsubstituted indole and various aromatic aldehydes in the presence of Red-Sea Dolomite mineral as an economical, recyclable, easily obtained, and nontoxic catalyst under solvent-free conditions. The molecular docking study explained that the bis-indolyl methane can be considered as a small molecule stimulator of HIV-1 frameshifting and inhibitor of viral replication.
 
 KEY WORDS: Indole, Dolomite, HIV-1, Catalyst, Frameshifting, Viral replication
 
 Bull. Chem. Soc. Ethiop. 2021, 35(3), 647-657.
 DOI: https://dx.doi.org/10.4314/bcse.v35i3.15

Effect of N-benzyl group in indole scaffold of thiosemicarbazones on the biological activity of their Pd(II) complexes: DFT, biomolecular interactions, in silico docking, ADME and cytotoxicity studies

A series of N-benzyl substituted indole-based thiosemicarbazone (TSC) ligands (L4-L6) and palladium(II) TSC complexes, [Pd(L)2] (1–6) (L = monoanionic bidentate un/N-substituted indole-based TSC ligand) have been synthesized and characterized using analytical and spectroscopic tools. The exact molecular structures of L4-L6 and the complexes (2–4 and 6) were ascertained by single-crystal X-ray diffraction (XRD) method. Spectroscopic and crystallographic studies indicated that Pd(II) ion was coordinated with TSCs as monobasic bidentate ligands, forming two five-membered rings with square planar geometry. The effect of N-benzyl substitution in indole scaffold of TSCs in the complexes was studied using DFT method, and structure–activity relationships (SAR) were explored. The in silico ADME properties of the ligands and their complexes were thoroughly analyzed with respect to their lipophilicity and oral bioavailability. The complexes (1–6) exhibited strong intercalation with calf thymus DNA (CT DNA), which was examined by absorption/emission spectroscopic titrations and viscosity measurements. Similarly, the interaction of bovine serum albumin (BSA) with complexes examined using spectroscopic methods showed a strong binding between them. A better picture of various possible interactions was acquired from the molecular docking of the complexes with the targets like DNA, BSA, DNA Topoisomerase II and CASP3. In addition, in vitro cytotoxicity of the complexes was screened against two cancer (HeLa-S3 and A549) and one normal (IMR-90) cell lines. It was learnt that the N-benzyl substitution in the indole system inactivated the whole molecule by diminishing its anticancer activity. The unsubstituted indole TSC complex (2) displayed significant activity towards HeLa-S3 cells, and the results were compared with those of cisplatin. Beneficially, the active complex showed less toxicity against IMR-90 normal cells. Further, the results of AO-EB staining studies indicated that the complexes induced cell death via apoptosis pathway. The steric influence of the substituted indole moiety, its limited electronic effects and lesser stability in aqueous systems retarded the Pd(II) complexes of N-benzyl substituted indole TSCs from exhibiting their biological activities.

Structure-Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections.

Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nucleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thiophene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide portion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 µM. Although the most active novel derivatives were also associated with an increased cytotoxicity in the human cell line, these compounds represent a very promising starting point for the development of new analogues with reduced cytotoxicity and improved selectivity indexes. In addition, the experimental biological data have been used to create an initial 3D quantitative structure-activity relationship model, which could be used to guide the future design of novel potential anti-norovirus agents.

Luminescence properties of 5-Bromoindole in PVA films at room temperature: Direct triplet state excitation

We studied spectral properties of 5-Bromoindole (5-BrI) in poly (vinyl alcohol) (PVA) film. The fluorescence of 5-BrI in PVA films is similar to indole in PVA film but strongly quenched compared to unsubstituted indole. The quantum yield of 5-BrI is only 0.0034 comparing to 0.26 of indole. In contrast, phosphorescence of 5-BrI in PVA is comparable to indole phosphorescence in magnitude and lifetime but its emission shifted towards longer wavelengths by 50 nm for a maximum at 530 nm. The phosphorescence of 5-BrI in PVA can be effectively excited at longer wavelengths (450–500 nm). The maximum of phosphorescence excitation spectrum of the 5-BrI in PVA is at about 480 nm. This direct excitation to the triplet state results in high positive phosphorescence anisotropy of 0.2. Although the S0 → T1 absorption transition is only about 800 fold weaker from the main 280 nm UV absorption band yielding measurable trace of absorption for 5-BrI in PVA film in the visible/blue range. We believe this is a first report of singlet-triplet absorption (S0 → T1) at room temperature, not involving external heavy atoms or oxygen presence. The comparison of phosphorescence of 5-BrI in PVA film to Rhodamine 6G in ethanol fluorescence allows us to estimate the phosphorescence quantum yield of 5-BrI in PVA to be ~0.02. We measured independently fluorescence and phosphorescence lifetimes and quantum yields as well as phosphorescence excitation spectrum across all wavelengths from UV to the visible range. These measurements were used to determine rate constants for all processes involved the in 5-BrI in PVA excited state deactivation.

Monoamine Oxidase (MAO-N) Biocatalyzed Synthesis of Indoles from Indolines Prepared via Photocatalytic Cyclization/Arylative Dearomatization

The biocatalytic aromatization of indolines into indole derivatives exploiting monoamine oxidase (MAO-N) enzymes is presented. Indoline substrates were prepared via photocatalytic cyclization of arylaniline precursors or via arylative dearomatization of unsubstituted indoles and in turn chemoselectively aromatized by the MAO-N D11 whole cell biocatalyst. Computational docking studies of the indoline substrates in the MAO-N D11 catalytic site allowed for the rationalization of the biocatalytic mechanism and experimental results of the biotransformation. This methodology represents an efficient example of biocatalytic synthesis of indole derivatives and offers a facile approach to access these aromatic heterocycles under mild reaction conditions.

Synthesis of Raputimonoindoles A–C and Congeners

The first synthesis of raputimonoindole A from the tree Raputia praetermissa (Rutaceae) is reported, starting from indole‐5‐carbaldehyde. The key step is Braun′s diastereoselective Heck–Suzuki cascade that assembled the prenylated methylenetetrahydrofuran moiety. The unsubstituted indole enamine functionality was tolerated, and the absolute configuration of naturally occurring raputimonoindole A is assigned as (R,R). Raputimonoindole B was accessed by Ir‐catalyzed C–H activation/borylation followed by Suzuki–Miyaura cross‐coupling. Two biosynthetically related 5‐(dihydrofuran‐2‐yl)indole derivatives from R. simulans were synthesized by ring‐closing metathesis, and their absolute configurations were determined.

Synthesis of novel pyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands

The study enabled obtaining a number of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine 9.1–9.27 having conformationally restricted tryptamine moiety. In vitro studies (RBA) have shown that derivatives 9.1, 9.2, 9.4, 9.7, 9.9, 9.14 and 9.27 exhibit high affinity to molecular targets 5-HT1A receptor and SERT protein. In general, compounds with an unsubstituted or a para-substituted benzene ring of the pyrido[1,2-c]pyrimidine residue in the terminal part were characterized by higher binding ability, which can be justified by the greater flexibility of the structure. For the selected compounds 9.1, 9.7, 9.9 and 9.27, further in vitro, in vivo and metabolic stability tests were performed. The in vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) indicated their selectivity toward the 5-HT1A receptor and SERT protein. The in vivo studies (8-OH-DPAT-induced hypothermia in mice, FST) revealed that the compound 9.1 has the properties of presynaptic agonist of the 5-HT1A receptor, and compound 9.7 demonstrated the properties of a presynaptic antagonist of the 5-HT1A receptor. Metabolic stability studies, in turn, showed that compounds 9.1, 9.7 and 9.9, having an unsubstituted indole residue, were more resistant to biotransformation reactions of the first pass phase than was compound 9.27 containing a 5-methoxy-substituted indole residue. The obtained results allowed further optimization of the structure.

Nickel-Catalyzed Regioselective C(2)-H Difluoroalkylation of Indoles with Difluoroalkyl Bromides.

Regioselective C(2)-H difluoroalkylation of C-3 unsubstituted indoles with commonly available fluoroalkyl bromides is successfully achieved employing a simple nickel catalyst system, (DME)NiCl2 /Xantphos. This methodology shows excellent regioselectivity and exhibits a broad substrate scope. Various functional groups, such as -OMe, -F, and -Br, are tolerated on the indole backbone to give the difluoroalkylated products in moderate to good yields. Preliminary mechanistic findings demonstrate that the reaction is homogeneous in nature and involves a radical manifold. Synthetic utility of this nickel-catalyzed method is demonstrated by synthesizing melatonin receptor antagonist Luzindole derivative.

Straight Access to Indoles from Anilines and Ethylene Glycol by Heterogeneous Acceptorless Dehydrogenative Condensation.

The development of original strategies for the preparation of indole derivatives is a major goal in drug design. Herein, we report the first straight access to indoles from anilines and ethylene glycol by heterogeneous catalysis, based on an acceptorless dehydrogenative condensation, under noninert conditions. In order to achieve high selectivity, a combination of Pt/Al2O3 and ZnO have been found to slowly dehydrogenate ethylene glycol generating, after condensation with the amine and tautomeric equilibrium, the corresponding pyrrole-ring unsubstituted indoles.

Brønsted acidic ionic liquid-promoted direct C3-acylation of N-unsubstituted indoles with acid anhydrides under microwave irradiation

A green and efficient method for the synthesis of 3-acylindoles using a Brønsted acidic ionic liquid under microwave irradiation has been developed.

A rapid and specific method for the detection of indole in complex biological samples.

Indole, a bacterial product of tryptophan degradation, has a variety of important applications in the pharmaceutical industry and is a biomarker in biological and clinical specimens. Yet, specific assays to quantitate indole are complex and require expensive equipment and a high level of training. Thus, indole in biological samples is often estimated using the simple and rapid Kovács assay, which nonspecifically detects a variety of commonly occurring indole analogs. We demonstrate here a sensitive, specific, and rapid method for measuring indole in complex biological samples using a specific reaction between unsubstituted indole and hydroxylamine. We compared the hydroxylamine-based indole assay (HIA) to the Kovács assay and confirmed that the two assays are capable of detecting microgram amounts of indole. However, the HIA is specific to indole and does not detect other naturally occurring indole analogs. We further demonstrated the utility of the HIA in measuring indole levels in clinically relevant biological materials, such as fecal samples and bacterial cultures. Mean and median fecal indole concentrations from 53 healthy adults were 2.59 mM and 2.73 mM, respectively, but varied widely (0.30 mM to 6.64 mM) among individuals. We also determined that enterotoxigenic Escherichia coli strain H10407 produces 3.3 ± 0.22 mM indole during a 24-h period in the presence of 5 mM tryptophan. The sensitive and specific HIA should be of value in a variety of settings, such as the evaluation of various clinical samples and the study of indole-producing bacterial species in the gut microbiota.

Palladium-Catalyzed Regioselective Alkynylation of Pyrroles and Azoles under Mild Conditions: Application to the Synthesis of a Dopamine D-4 Receptor Agonist.

A mild and general method for the direct alkynylation of azoles such as pyrrole, indole, and 7-azaindole is described here. Using a simple catalytic system such as Pd(OAc)2 (2.5 mol %), P(tBu)2Me·HBF4 (5 mol %), and NaOAc (2 equiv) allowed the regioselective introduction of various alkynyl residues at the C-2 position of pyrroles. Interestingly, C-2 alkynylation was also observed on C-3-substituted indoles, whereas classical C-3 alkynylation was obtained on selected unsubstituted indoles and 7-azaindole. Our methodology has been illustrated by the efficient synthesis of a potential schizophrenia drug (dopamine D-4 inhibitor).

ChemInform Abstract: Pd‐Catalyzed C—H Carbonylation of (Hetero)arenes with Formates and Intramolecular Dehydrogenative Coupling: A Shortcut to Indolo[3,2‐c]coumarins.

AbstractThe reaction tolerates N‐protected and N‐unprotected, substituted and unsubstituted indole derivatives as well as arenes and heteroarenes such as indolizines, pyrroles and electron rich benzol derivatives.

ChemInform Abstract: N1‐Selective Oxidative C—N Coupling of Azoles with Pyrroles Using a Hypervalent Iodine Reagent.

AbstractNo explanation is given for the changed regioselectivity in the reaction of triazole (VIII) with unsubstituted indole (XV).

ChemInform Abstract: Extending the Versatility of the Hemetsberger—Knittel Indole Synthesis Through Microwave and Flow Chemistry.

AbstractA wide range of substituted and unsubstituted indoles and heterocyclic variants are obtained by microwave mediated Hemetsberger—Knittel cyclizations and tandem cyclization‐decarboxylation.

Manganese Chloride as an Efficient Catalyst for Selective Transformations of Indoles in the Presence of a Keto Carbonyl Group

AbstractCatalysis by manganese chloride tetrahydrate was found to be effective for the selective transformation of indoles, with which the desired acid‐catalyzed reaction could be promoted and, at the same time, a side reaction that also needs assistance of acid, the electrophilic reaction of indole with the co‐existing keto carbonyl group, does not occur. Some acid‐catalyzed reactions, such as the ring‐opening reaction of 2‐alkoxy‐3,4‐dihydropyran with indole, and transesterification of β‐keto ester with an alcohol that contains a C‐3 unsubstituted indole fragment, could be performed smoothly by using manganese chloride as catalyst. A new multicomponent reaction of indole, 3,4‐dihydropyran and β‐keto ester was also developed with catalysis by manganese chloride.

3-Substitued indoles: One-pot synthesis and evaluation of anticancer and Src kinase inhibitory activities

An efficient and economical method was developed for the synthesis of 3-substituted indoles by one-pot three-component coupling reaction of a substituted or unsubstituted benzaldehyde, N-methylaniline, and indole or N-methylindole using Yb(OTf)(3)-SiO(2) as a catalyst. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), human ovarian adenocarcinoma (SK-OV-3), and c-Src kinase activity. The 4-methylphenyl (4o and 4p) and 4-methoxyphenyl (4q) indole derivatives inhibited the cell proliferation of SK-OV-3 and HT-29 cells by 70-77% at a concentration of 50 μM. The unsubstituted phenyl (4d) and 3-nitrophenyl (4l) derivatives showed the inhibition of c-Src kinase with IC(50) values of 50.6 and 58.3 μM, respectively.