Indole Derivatives Research Articles

Copper-Catalyzed Intramolecular Decarboxylative C(sp2)-Heteroatom Cross-Couplings: Mechanism Insights and Synthetic Applications.

Decarboxylative C(sp2)-heteroatom cross-coupling reactions hold extraordinary potential for the sustainable preparation of biologically active scaffolds. Herein, we report a copper sulfate/1,10-phenathroline catalytic system for the decarboxylative intramolecular C(sp2)-O, C(sp2)-S, and C(sp2)-N coupling reactions leading to the construction of a series of benzo[b]furans, benzo[b]thiophenes, and indole derivatives from the corresponding coumarins, thiocoumarins, or quinolones, respectively. Our mechanistic study based on benzo[b]furan formation suggests a three-step process of the transformations, which consists of (i) base-mediated hydrolytic ring opening of coumarin, (ii) copper-oxygen co-initiated radical decarboxylation, and (iii) copper-catalyzed C-heteroatom cross coupling. Application of this method in the total synthesis of egonol, a bioactive natural product, was demonstrated successfully, with an overall yield of 51.7%.

Palladium-Catalyzed Denitrative α-Arylation of Heteroarenes with Nitroarenes via C-H and C-NO2 Bond Activations.

A general approach for the α-arylation of heteroarenes with nitroarenes via denitrative coupling is reported for the first time. Various heteroarenes, including derivatives of furan, benzofuran, pyrrole, indole, thiophene, and benzothiophene, can be arylated at the α-position in moderate to good yields. Mechanistic studies demonstrate that the reaction proceeds via a CMD pathway, with C-H bond activation as the rate-determining step. Furthermore, the scalability and applicability in the synthesis of a drug molecule exemplify the utility of this protocol.

Rh-Catalyzed C-H Alkynylation of Indole Derivatives with Silver(I)-Controlled Regiodivergence.

We have disclosed silver(I)-induced switching of regioselectivity in rhodium-catalyzed C-H alkynylation of indole derivatives with the help of a pivaloyl directing group by tuning C-H metalation modes. The judicious choice of AgOAc, Ag2O, and Ag2CO3 affords an array of C2-alkynylated indoles, C4-alkynylated indoles, and C2,C4-dialkynylated indoles, respectively. The synthetic utility of the alkyne fragment is demonstrated by derivatization into valuable indole-based compounds.

A probiotic Limosilactobacillus fermentum GR-3 mitigates colitis-associated tumorigenesis in mice via modulating gut microbiome

Bacterial therapy for colorectal cancer (CRC) represents a burgeoning frontier. The probiotic Limosilactobacillus fermentum GR-3, derived from traditional food “Jiangshui”, exhibited superior antioxidant capacity by producing indole derivatives ICA and IPA. In an AOM/DSS-induced CRC mouse model, GR-3 treatment alleviated weight loss, colon shortening, rectal bleeding and intestinal barrier disruption by reducing oxidative stress and inflammation. GR-3 colonization in distant colon induced apoptosis and reduced tumor incidence by 51.2%, outperforming the control strain and vitamin C. The beneficial effect of GR-3 on CRC was associated with gut microbiome modulation, increasing SCFA producer Lachnospiraceae NK4A136 group and suppressing pro-inflammatory strain Bacteroides. Metagenomic and metabolic analyses revealed that GR-3 intervention upregulated antioxidant genes (xseA, ALDH) and butyrate synthesis gene (bcd), while increasing beneficial metabolites (SCFAs, ICA, IPA, VB12 and VD3) and reducing harmful secondary bile acids. Overall, GR-3 emerges as a promising candidate in CRC therapy, offering effective gut microbiome remediation.

The role of gut microbiota metabolites in the regeneration and protection of nervous tissue: a narrative review

The gut microbiota modulates various physiological functions in the human body, including digestion, immune regulation, gut barrier maintenance, and even nervous system activity. The bidirectional communication between gut microbes and the brain, known as the microbiota–gut–brain axis, is crucial for balanced metabolism. Recent studies have indicated that gut microbiota metabolites, such as short-chain fatty acids, indole derivatives, neurotransmitters, and other bioactive compounds, can positively impact neurogenesis, myelination, and axonal regeneration, suggesting their potential in therapeutic strategies for neuroprotection and neuroregeneration. Despite the growing number of studies on gut microbiota metabolites, understanding their role in neuroprotective mechanisms remains limited. This article reviews the classification, production, functions and therapeutic potential of the most well-known gut microbiota metabolites, as well as their impact on neurogenesis, synaptogenesis, energy metabolism, immune modulation, and blood–brain barrier integrity, which will provide a foundation for the study of gut microbiota metabolites in the field of biomedical engineering.

Microwave-assisted synthesis of some new 2-(substituted phenyl)-3-(thiazol-2-yl)imidazo[4,5-b]indoles of biological interest

In the present investigation, we have synthesized some new 2-(substituted phenyl)-3-(thiazol-2-yl) imidazo[4,5-b]indoles (1b-8b) of biological interest. In the last step of the synthesis, N-(substituted benzylidene)thiazole-2- amines (1a-8a) were reacted with isatin and ammonium acetate using silica gel as the solid support to yield the corresponding substituted thiazolyl imidazo indole derivatives (1b-8b). The reactions were carried out by two different techniques - conventional and microwave irradiation. The microwave irradiation method offers excellent yield, lesser reaction time, and eco-environmental friendly reaction. All the synthesized compounds showed anticancer (Dalton lymphoma ascites cell line and EAC cell line method) and antibacterial activity (cup plate method).. KEYWORDS :Thiazolyl imidazo indole, Microwave-assisted synthesis, Anticancer, Antibacterial.

New hydrazide-hydrazone derivatives containing coumarin and indole moiety: Synthesis, spectroscopic characterization and DFT studies

Two new compounds (3 and 4), coumarin indole derivatives with a hydrazide-hydrazone skeleton, were synthesized, and their spesctroscopic properties, including UV-vis, FTIR, and 1H-13C NMR were investigated experimentally and theoretically. The experimental data and DFT (density functional theory) results of the compounds matched well and showed good agreement. Moreover, the DFT/B3LYP/6-311G++(2d,p) calculations were utilized to perform HOMO and LUMO energy, net atomic charges, MEP surface, and NBO analysis for the optimized geometries of 3 and 4. NBO analysis revealed that the synthesized compounds exhibit high molecular stability because of significant hyperconjugative interactions. The experimental and theoretical band gaps (ΔEg) investigated in some organic solvents with different polarities were determined to be in the range of 2.68-2.75 eV and 3.22-3.25 eV for compound 3, and 2.69-2.77 eV and 3.41-3.47 eV for compound 4, respectively. The compounds demonstrated thermal stabilities with a Td value higher than 300 °C.

Synthesis of Novel 6H‐Furo[3,2‐e]Indole Derivatives via One‐Pot Three Component Reactions

ABSTRACTA one‐pot, three‐component reaction of ethyl 5‐aminobenzofuran‐2‐carboxylate, arylglyoxals and cyclic 1,3‐dicarbonyl compounds in the presence of acetic acid as an organocatalyst in ethanol medium under reflux conditions provided a series of new 6H‐furo[3,2‐e]indole derivatives in good yields.

Structural Reassignment of Covalent Organic Framework-Supported Palladium Species: Heterogenized Palladacycles as Efficient Catalysts for Sustainable C-H Activation.

Recent decades have witnessed remarkable progress in ligand-promoted C-H activation with palladium catalysts. While a number of transformations have been achieved with a fairly broad substrate scope, the general requirements for high palladium loadings and enormous challenges in catalyst recycling severely limit the practical applications of C-H activation methodologies in organic synthesis. Herein, we incorporate N,C-ligand-chelated palladacycles into rigid, porous, and crystalline covalent organic frameworks for the C-H arylation of indole and pyrrole derivatives. These heterogeneous palladium catalysts exhibit superior stability and recyclability compared to their homogeneous counterparts. We not only produce several highly reactive palladacycles embedded on new framework supports to facilitate C-H activation/C-C bond-forming reactions but also reassign heterogenized palladium species on frameworks containing a benzaldehyde-derived imine moiety as imine-based palladacycles via comprehensive characterization. Our findings provide guidance for the rational design of framework-supported metallacycles in the development of heterogeneous transition-metal catalysis.

Antiangiogenic activity of 5-bromoindole carbothioamide derivative in ex vivo, in vivo, and in vitro experimental study

The study aimed to investigate the antiangiogenic, antioxidant, and cytotoxicity activity of a carbothioamide indole derivative. The 2-NPHC activity was evaluated using the ex vivo rat aorta ring assay, the in vivo chick chorioallantois membrane assay, the DPPH assay for scavenging activity, and the expression of the VEGF gene in colon cancer cell line (HCT116). The 2-NPHC had significant antiangiogenic activity in a dose-dependent manner in the rat aorta assay. 2-NPHC managed to reduce the DPPH free radical in a concentration-dependent, 2-NPHC had low to non-toxic effects on the HUVEC cell line, with an IC50 value of 711.7 μg/ml. The VEGF gene expression in the HCT116 cell line reduced the target gene expression compared to control cells. In conclusion, 2-NPHC exhibited significant inhibition of the angiogenesis process, either directly by inhibiting the release or activity of VEGF or indirectly through its antioxidant properties.

A Promising Paradigm Shift in Cancer Treatment with FGFR Inhibitors.

FGFR have been demonstrated to perform a crucial role in biological processes but their overexpression has been perceived as the operator component in the occurrence and progression of different types of carcinoma. Out of all the interest around cancer, FGFR inhibitors have assembled pace over the past few years. Therefore, FGFR inhibitors are one of the main fundamental tools to reverse drug resistance, tumor growth, and angiogenesis. Currently, many FGFR inhibitors are under the development stage or have been developed. Due to great demand and hotspots, different pharmacophores were approached to access structurally diverse FGFR inhibitors. Here, we have selected to present several representative examples such as Naphthyl, Pyrimidine, Pyridazine, Indole, and Quinoline derivatives that illustrate the diversity and advances of FGFR inhibitors in medicinal chemistry. This review focuses on the SAR study of FGFR inhibitors last five years which will be a great future scope that influences the medicinal chemist to work towards more achievements in this area.

RGO/CuO NC catalyzed green synthesis, DFT studies, Mulliken atomic charge analysis and anti-inflammatory activity of indole derivatives

An admirable catalytic activity of as-prepared copper oxide decorated reduced graphene oxide nanocomposite (rGO/CuO NC) catalyst is reported in the synthesis of spiro[indoline-pyranothiazole]carbonitrile and thiazolopyranofuroindole derivatives. The excellent activity exhibited by hybrid nanocomposite is attributed to the synergistic effect of graphene oxide and copper oxide nanoparticles. The utilization of ultrasonication as energy source lead to enhanced mass transfer, and reaction rate expeditiousness in the presence of rGO/CuO NC forming spiro/condensed indole derivatives. 100% conversion is observed on Thin Layer Chromatography (TLC). The recovered rGO/CuO NC can be reused for four uninterrupted cycles without substantial loss in its catalytic activity. DFT (Density functional theory) studies, Mulliken atomic charge analysis and anti-inflammatory activity of the synthesized spiro/condensed indole derivatives have also been evaluated.

Interplay between gut microbiota and tryptophan metabolism in type 2 diabetic mice treated with metformin.

This study provides valuable insights into the interrelationship between metformin administration, changes in the tryptophan (TRP) metabolome, and gut microbiota in type 2 diabetes mellitus (T2DM) mice. Indole-3-lactic acid (ILA)/indole-3-propionic acid (IPA) emerges as a potential biomarker for the development of T2DM and prediction of therapeutic response. While the indole metabolic pathway has long been associated exclusively with the gut microbiome, recent research has demonstrated the ability of host interleukin-4-induced-1 to metabolize TRP. The detection of indole derivatives in the serum of germ-free mice suggests the existence of inherent endogenous indole metabolic pathways. These findings deepen our understanding of metformin's efficacy in correcting TRP metabolic disorders and provide valuable directions for further investigation. Moreover, this knowledge may pave the way for the development of targeted treatment strategies for T2DM, focusing on the gut microbiome and restoration of associated TRP metabolism.

Indole derivatives efficacy and kinetics for inhibiting carbon steel corrosion in sulfuric acid media

The global prevalence of metal corrosion is a significant challenge due to its detrimental effect. Environmentally friendly and non-hazardous alternatives for harmful and poisonous synthetic corrosion inhibitors are urgently necessary due to increasing environmental concerns and regulations prohibiting their application. In this study, indole molecules were employed as carbon steel corrosion inhibitors in acidic conditions. Gravimetrical and scanning electronic microscope (SEM) analysis was used in a preliminary investigation of indole as an organic inhibitor. The results revealed that adding indole to carbon steel before exposing it to sulfuric acid slowed and induced resistance to corrosion. The indole affixed themselves to the steel carbon surfaces, producing a barrier/protection for carbon steel. The efficacy of the indole in preventing corrosion was determined through the weight loss method. Temperature and inhibitory concentration effects on inhibition effectiveness under varying parameters were also reported. The temperatures employed were between 298 K and 328 K, while the inhibitor concentrations ranged from 1.2 × 10−3 M to 7.6 × 10−3 M, and both parameters significantly influenced corrosion inhibition effectiveness. The inhibitory mixture attained optimum efficacy in inhibiting corrosion, at 81 %, when the lowest and highest respective temperature and concentration were applied. The kinetic analysis was conducted under a range of temperatures to determine the reaction mechanisms of the inhibitor. The thermal adsorption isotherm of the inhibitor indicated that the surface adhered to Langmuir's adsorption isotherm. Additionally, investigations on corrosion and inhibition using the electrochemical impedance spectroscopy method (EIS) were conducted. This study can provide in-depth knowledge for advancing inhibitory science and engineering to enhance corrosion resistance in acidic media.

Nickel-Catalyzed Radical Hydroalkylative Dearomatization of Indoles with Alkyl Bromides

Dearomatization of indole derivatives offers a straightforward approach to accessing indoline framework. However, highly efficient dearomatization of indoles bearing electron-deficient groups remains underdeveloped. Herein, a nickel-catalyzed intermolecular hydroalkylative dearomatization reaction of indoles with simple alkyl bromides via single-electron-transfer process is reported. A wide variety of indole derivatives bearing versatile functional groups were compatible with this protocol, by reacting with primary, secondary, and tertiary bromides to afford a series of indolines in good yields (up to 82%) with excellent diastereoselectivity (up to >20:1). Notably, a nickel-mediated hydrogen atom transfer process was observed when terminal bromides were employed as the radical precursors, which resulted in the branched products.

Formation of Bis‐indolylmethanes from Symmetrical Triarylmethanes via Brønsted Acid Catalyzed C−C Bond Breaking Reaction

AbstractAn alternative approach to synthesize bis‐indolylmethanes (BIMs) via a unique p‐toluenesulfonic acid (PTSA) catalyzed dual Csp3−Csp2 bond‐breaking reaction has been reported here. In the reported protocol, 1,3,5‐trimethoxybenzene (TMB), an electron‐rich and sterically bulky arene, acts as a carbon‐based leaving group which can be recovered after the completion of the reaction. In this process, several BIMs of various indole derivatives can be synthesized from symmetrical triarylmethanes (TRAMs) containing bis‐TMB motifs. By modifying the reaction conditions, we could control the sequential bond cleavage of two Csp3−Csp2 bonds in starting TRAM.

Regioselective Synthesis of 2,3-Disubstituted Indoles via Interrupted Heyns Rearrangement Involving C-C Bond Cleavage.

A novel metal free, Brønsted acid mediated and operationally simple strategy has been developed for regioselective synthesis of 2,3-disubstituted indoles from α-hydroxyketones and o-aminoaryl ketones in excellent yields. The reaction proceeds via interrupted Heyns rearrangement through the generation of aminoenol intermediate followed by intramolecular trapping and aromatization with C-C bond cleavage and release of corresponding ester. The mechanism was further supported by the identification of ester in GCMS and reaction of cyclic α-hydroxydimethylketal, which afforded ester tethered indole derivative.

Fast Targeted Metabolomics for Analyzing Metabolic Diversity of Bacterial Indole Derivatives in ME/CFS Gut Microbiome.

Disruptions in microbial metabolite interactions due to gut microbiome dysbiosis and metabolomic shifts may contribute to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and other immune-related conditions. The aryl hydrocarbon receptor (AhR), activated upon binding various tryptophan metabolites, modulates host immune responses. This study investigates whether the metabolic diversity-the concentration distribution-of bacterial indole pathway metabolites can differentiate bacterial strains and classify ME/CFS samples. A fast targeted liquid chromatography-parallel reaction monitoring method at a rate of 4 minutes per sample was developed for large-scale analysis. This method revealed significant metabolic differences in indole derivatives among B. uniformis strains cultured from human isolates. Principal component analysis identified two major components (PC1, 68.9%; PC2, 18.7%), accounting for 87.6% of the variance and distinguishing two distinct B. uniformis clusters. The metabolic difference between clusters was particularly evident in the relative contributions of indole-3-acrylate and indole-3-aldehyde. We further measured concentration distributions of indole derivatives in ME/CFS by analyzing fecal samples from 10 patients and 10 healthy controls using the fast targeted metabolomics method. An AdaBoost-LOOCV model achieved moderate classification success with a mean LOOCV accuracy of 0.65 (Control: precision of 0.67, recall of 0.60, F1-score of 0.63; ME/CFS: precision of 0.64, recall of 0.7000, F1-score of 0.67). These results suggest that the metabolic diversity of indole derivatives from tryptophan degradation, facilitated by the fast targeted metabolomics and machine learning, is a potential biomarker for differentiating bacterial strains and classifying ME/CFS samples. Mass spectrometry datasets are accessible at the National Metabolomics Data Repository (ST002308, DOI: 10.21228/M8G13Q; ST003344, DOI: 10.21228/M8RJ9N; ST003346, DOI: 10.21228/M8RJ9N).

Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice

Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.

Synthesis, Characterization, and Docking Study of a Novel Indole Derivative Containing a Tosyl Moiety as Anti-Oxidant Agent

Synthesis, Characterization, and Docking Study of a Novel Indole Derivative Containing a Tosyl Moiety as Anti-Oxidant Agent