Indole Derivatives Research Articles

Tosylazide as N1-Synthon: Iron-Catalyzed Nitrogenative Dimerization of Indoles to p-Bisindolopyrazine Derivatives.

We present a straightforward one-step process to access a range of novel p-diindolepyrazines via an unprecedented [n-Bu4N][Fe(CO)3(NO)] (TBA[Fe])-catalyzed intermolecular nitrogenative dimerization of various indole derivatives. Remarkably, tosylazide functions as a N1-synthon forming the central pyrazine unit that joins the two indole subunits. The catalytic transformation shows a good substrate scope, and the obtained products show interesting electronic properties.

Discovery of small molecule benzothiazole and indole derivatives tackling tau 2N4R and α-synuclein fibrils

Tau and α-synuclein aggregates are the main histopathological hallmarks present in Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative disorders. Intraneuronal hyperphosphorylated tau accumulation is significantly connected to the degree of cognitive impairment in AD patients. In particular, the longest 2N4R tau isoform has a propensity to rapidly form oligomers and mature fibrils. On the other hand, misfolding of α-synuclein (α-syn) is the characteristic feature in PD and dementia with Lewy bodies (DLB). There is a strong crosstalk between the two prone-to-aggregation proteins as they coprecipitated in some brains of AD, PD, and DLB patients. Simultaneous targeting of both proteinaceous oligomers and aggregates is still challenging. Here, we rationally designed and synthesized benzothiazole- and indole-based compounds using the structural hybridization strategy between the benzothiazole N744 cyanine dye and the diphenyl pyrazole Anle138b that showed anti-aggregation activity towards 2N4R tau and α-syn, respectively. The anti-aggregation effect of the prepared compounds was monitored using the thioflavin-T (ThT) fluorescence assay, while transmission electron microscopy (TEM) was employed to detect fibrils upon the completion of a time-course study with the ThT assay. Moreover, the photo-induced crosslinking of unmodified protein (PICUP) assay was used to determine the formation of oligomers. Specifically, compounds 46 and 48 demonstrated the highest anti-aggregation activity by decreasing the ThT fluorescence to 4.0 and 14.8%, respectively, against α-syn. Although no noticeable effect on 2N4R tau oligomers, 46 showed promising anti-oligomer activity against α-syn. Both compounds induced a significantly high anti-aggregation effect against the two protein fibrils as visualized by TEM. Moreover, compound 48 remarkably inhibited α-syn inclusion and cell confluence using M17D cells. Collectively, compounds 46 and 48 could serve as a basic structure for further optimization to develop clinically active AD and PD disease-modifying agents.

Copper‐Mediated Cross‐Dehydrogenative Coupling Reaction of Pyrrole and Indole Derivatives with Thiols

AbstractA copper‐mediated C(sp2)−H thiolation of pyrrole and indole derivatives with commercially available thiols utilizing a removable monodentate directing group is described. This protocol tolerated a broad range of functional groups and provided the thiolated products in 40 %–97 % yields. Furthermore, the synthetic utility of this protocol was demonstrated by the late‐stage functionalization of bioactive tryptophan peptide. Preliminary mechanistic studies indicated that a Cu(II)/Cu(III) reaction model is most likely to be involved in this C−H thiolation.

Weak‐Chelation Assisted Regioselective Indole C(4)‐Alkynylation via Six‐Membered Cobaltacycle Intermediate

AbstractHerein a regioselective indole C4‐alkynylation has been uncovered utilizing an earth‐abundant cobalt(III)‐catalyst. For this process, (bromoethynyl)benzene was used as an alkynylating agent. Also, after screening various amide‐protected chelating groups we found dimethyl‐amide is optimal for the in‐situ generation of cobaltacycle intermediate. The six‐membered cobaltacycle intermediate has been detected through high‐resolution mass spectrometry HRMS, which is a key intermediate for this conversion. Further, mechanistic studies were performed such as KIE experiments, and reactions with radical scavengers, and based on the results a plausible mechanism has been proposed. Moreover, to show the application of this methodology, the product has been oxidized to diketone, monoketone, alkene, alkane and further derivatized to a tricycle indole derivative, which is a core structure of many natural products.

Selective Functionalization of Indole: Synthesis of Bioinspired 2,2′‐thiobisindoles, 3‐substituted Oxindoles, and 1‐(chloromethyl) Indoline‐2‐dione in One‐pot manner

AbstractIndolyl thioethers and indolin‐2‐one motifs are extremely common in pharmaceuticals and organic materials, therefore developing a method to create these scaffolds is considered to be a vital endeavour in the chemical sciences. Here we have reported a unified strategy developed by the fine‐tuning of catalyst‐solvent combination [SOCl2 /AlCl3 in CHCl3 and SOCl2/DMSO (1 : 1) in CHCl3 at 25 °C] towards selective functionalization of Indole to synthesize 2,2′‐thiobisindoles and 3‐chloro‐3‐alkyl substituted oxindoles selectively in one‐pot manner with good to satisfactory yield (52‐86 %; 26 Examples). In application, reactions of 3‐subsituted indole and isatin derivatives produced the 1‐(chloromethyl) indoline‐2,3‐diones by just changing the reaction condition (60 °C), which shows the synthetic utility of the developed method.

Lysine-Specific Demethylase 1 Inhibitors: A Comprehensive Review Utilizing Computer-Aided Drug Design Technologies.

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.

Synthesis and investigation of new indole-containing vinyl sulfide derivatives: In silico and in vitro studies for potential therapeutic applications.

Indoles featuring organosulfur compounds serve as privileged structural scaffolds in various biologically active compounds. This study investigates the biological properties of five synthetic sulphenyl vinyl indoles (3 a-e) using both in silico and in vitro methods. Computational analyses employing Swiss ADME and Molinspiration software reveal the remarkable inhibitory activity of compound 3 d against proteases and kinases (scores of 0.18 and 0.06, respectively). Furthermore, it demonstrates the ability to modulate ionic and G protein-coupled receptors (scores: -0.06 and 0.31, respectively) and serves as a ligand for nuclear receptors (score 0.15). In vitro investigations highlight the compounds' efficacy in countering ABTS+ radical attacks and reducing lipid peroxidation levels. Particularly noteworthy is the superior efficacy of compounds 3 a, 3 b, and 3 e in DPPH (EC50 3 a: 268.5 μM) and TEAC assays (EC50 3 a: 49.9 μM; EC50 3 b: 133.4 μM, and EC50 3 e: 84.9 μM), as well as TBARS levels. Compound 3 c significantly reduces acetylcholinesterase activity, positioning itself as a noteworthy enzyme inhibitor. This study emphasizes the versatile biological potential of synthetic indole derivatives, suggesting their applicability for therapeutic purposes.

Visible-light-induced radical cascade cyclization: a catalyst-free synthetic approach to trifluoromethylated heterocycles.

A visible-light-promoted research protocol for constructing dihydropyrido[1,2-a]indolone skeletons is herein described proceeding through a cascade cyclization mediated by trifluoromethyl radicals. This method allows the efficient synthesis of various indole derivatives without the need of photocatalysts or transition-metal catalysts. Mechanism experiments indicate that the process involves a radical chain process initiated by the homolysis of Umemoto's reagent. This straightforward method enables a rapid access to heterocycles containing a trifluoromethyl group.

Reactivity and Stability of (Hetero)Benzylic Alkenes via the Wittig Olefination Reaction.

Wittig olefination at hetero-benzylic positions for electron-deficient and electron-rich heterocycles has been studied. The electronic effects of some commonly used protective groups associated with the N-heterocycles were also investigated for alkenes obtained in the context of the widely employed Wittig olefination reaction. It was observed that hetero-benzylic positions of the pyridine, thiophene and furan derivatives were stable after Wittig olefination. Similarly, electron-withdrawing groups (EWGs) attached to N-heterocycles (indole and pyrrole derivatives) directly enhanced the stability of the benzylic position during and after Wittig olefination, resulting in the formation of stable alkenes. Conversely, electron-donating group (EDG)-associated N-heterocycles boosted the reactivity of benzylic alkene, leading to lower yields or decomposition of the olefination products.

New indole derivatives from endophytic fungus Colletotruchum sp. HK-08 originated from leaves of Nerium indicum

ObjectiveTo study secondary metabolites from endophytic fungus Colletotruchum sp. HK-08 originated from the leaves of Nerium indicum. MethodsThe compounds were isolated by various column chromatographic techniques, and their structures were elucidated by spectroscopic techniques [high resolution electrospray ionization mass spectroscopy (HRESIMS), one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance spectroscopy (NMR)], as well as comparison with literature data. The Ellman method was used to determine the acetylcholinesterase (AChE) inhibitory activity. ResultsFour indole derivatives were identified from Colletotruchum sp. HK-08, including 6′-hydroxymonaspiloindole (1), 2-(2-oxoindolin-3-yl)ethyl 2-(4-hydroxyphenyl) acetate (2), 2-(2-oxoindolin-3-yl)ethyl 2-(2-hydroxyphenyl)acetate (3), and monaspiloindole (4). Compound 4 presented weak AChE inhibitory activity with IC50 value of (69.30 ± 6.27) μmol/L [tacrine as the positive control, with IC50 value of (0.61 ± 0.07) μmol/L]. ConclusionCompounds 1–3 were new compounds, and compound 4 had weak AChE inhibitory activity.

Nitro Indole Derivatives as Novel Dual-Polarity Matrices for MALDI Mass Spectrometry and Imaging with Broad Applications.

A new matrix framework is presented in this study for the improved ionization efficiency of complex mixtures by matrix-assisted laser desorption ionization (MALDI) mass spectrometry/imaging. Five nitro indole (NI) derivatives [3-methyl-4-nitro-1H-indole (3,4-MNI), 3-methyl-6-nitro-1H-indole (3,6-MNI), 2,3-dimethyl-4-nitro-1H-indole (2,3,4-DMNI), 2,3-dimethyl-6-nitro-1H-indole (2,3,6-DMNI), and 4-nitro-1H-indole (4-NI)] were synthesized and shown to produce both positive and negative ions with a broad class of analytes as MALDI matrices. NI matrices were compared to several common matrices, such as 2,5-dihydroxybenzoic acid (DHB), alpha-cyano-4-hydroxylcinnamic acid (CHCA), sinapinic acid (SA), 1,5-diaminonaphthelene (1,5-DAN), and 9-aminoacridine (9-AA), for the analysis of lipid, peptide, protein, glycan, and perfluorooctanesulfonic acid (PFOS) compounds. 3,4-MNI demonstrated the best performance among the NI matrices. This matrix resulted in reduced ion suppression and better detection sensitivity for complex mixtures, for example, egg lipids/milk proteins/PFOS in tap water, while 2,3,6-DMNI was the best matrix for blueberry tissue imaging. Several important aspects of this work are reported: (1) dual-polarity ion production with NI matrices and complex mixtures; (2) quantitative analysis of PFOS with a LOQ of 0.5 ppb in tap water and 0.05 ppb in MQ water (without solid phase extraction enrichment), with accuracy and precision within 5%; (3) MALDI imaging with 2,3,6-DMNI as a matrix for plant metabolite/lipid identification with ionization enhancement in the negative ion mode m/z 600-900 region; and (4) development of a thin film deposition under/above tissue method for MALDI imaging with a vacuum sublimation matrix on a high-vacuum MALDI instrument.

Photocatalytic Dehydrogenative 6π‐Photocyclisation of Indole Derivatives via Successive Energy Transfer

AbstractHerein, a successive energy transfer (sEnT) strategy to enable a dehydrogenative 6π‐photocyclisation, without the need for an external oxidant is reported, in which the energetically unfavourable dehydrogenation is driven by energy transfer. The valuable applicability of this method was demonstrated by the scaffold hopping of indole containing bioactive molecules, as well as by the succinct synthesis of naturally occurring tetracyclic furocarbazole alkaloids. Moreover, experimental and computational studies were conducted to elucidate the reaction mechanism.

Comparing the Effects of Free and Liposomal Indole Compounds on Bax and Bcl2 Gene Expression Changes in the KG-1 Cell Line

Background: For patients with acute myeloid leukemia (AML), the long-term survival rate is still very low. This study examines the effects on AML cell lines of an indole chemical in its free and liposomal forms. Material and Method: In this experimental case control study, an AML-originated KG-1 cell line was cultured in RPMI 1640 medium. The cells were treated with the free and liposomal forms of an indole compound (C18H10N2F6O) at different concentrations of 20, 40, 100, 200, and 400 µg/mL after they attained the proper confluence. The cellular metabolic activity was examined by an MTT assay. The expression of BAX and BCL-2 genes was investigated by q-PCR to assess the apoptotic effect of that compound. The analysis was also done between each experimental group and the control group using t-test. P<0.05 was assumed significant. Results: Based on the MTT assay, the lethal effective dose of free indole was found to be 245.1 µg/ml and 164.8 µg/ml in 24 and 48 hours, respectively. The corresponding values for liposomal indole were 47.2 µg/ml and 40.6 µg/ml. Furthermore, treatment with free and liposomal forms of indole resulted in a decline in the expression level of the BCL-2 gene. However, in the case of the liposomal compound, this decrease was only statistically significant after 48 hours of treatment (P < 0.05). Furthermore, the expression of BAX gene increased after treatment with both free and liposomal forms of indole, but it significantly increased only after treatment with the liposomal compound (p < 0.05). Conclusion: These results suggest that an indole derivative, especially when liposomal, causes apoptosis in AML cells, hence exhibiting cytotoxic effects. To confirm the potential usefulness of this indole derivative as a therapeutic agent for inhibiting tumor progression in the setting of human malignancies, more studies on physiologically relevant models are necessary.

CHROMATOGRAPHIC AND PHYTOBIOLOGICAL ASSESSMENT OF SOME NATURAL BORON-CONTAINING COMPOUNDS

Boron (B) has many roles in the plant kingdom, being an essential element for fundamental metabolic pathways, with reference to carbohydrates, ribonucleic acid, phenolic compounds, indole acetic acid derivatives, respiration, as well as for the structure of cell wall and integrity of plasma membrane, cell division, differentiation, and elongation at the level of meristematic tissues, growth of the pollen tube, grain maturation. It has also been shown that the low amount of B can cause sterility during herbal reproductive stage.For identification and quantitative determination of some natural B-containing compounds (BCCs), such as boric acid, fructoboric acid and its derivatives (Ca–fructose–B complex and Zn–fructose–B complex), sodium tetraborate, high-performance thin-layer chromatography (HPTLC)–ultraviolet (UV) densitometry method was used, based on the following experimental conditions: stationary phase HPTLC silica gel G 60 F254 precoated glass plates, mobile phase 2-propanol–water 8:2 (v/v), derivatization with chlorogenic acid.The phytobiological assessment of natural BCCs was carried out using Triticum test. A slight stimulation of the mean radicular elongation of wheat-germinated caryopses, compared to the reference, was recorded for fructoboric acid and its derivatives at a concentration of 0.1% expressed in B.

Palladium(ii) complexes bearing mesoionic carbene ligands: catalytic application in domino Sonogashira coupling/cyclization reactions for one-pot synthesis of benzofuran and indole derivatives.

Bioactive heterocycles such as benzofuran and indole derivatives were synthesized from commercially available 2-iodoarenes and alkynes via domino Sonogashira coupling followed by cyclization reaction using well-defined palladium PEPPSI (Pyridine Enhanced Precatalyst Preparation Stabilization and Initiation) complexes (2a and 2b). These reactions tolerate a variety of 2-iodoarenes and diversely substituted terminal alkynes, resulting in the corresponding product in moderate to good yields in an open-air atmosphere. In particular, two palladium(ii) PEPPSI complexes 2a and 2b were synthesized in good yields from the reaction of corresponding 1,2,3-triazol-5-ylidene (MIC: mesoionic carbene), PdCl2, KI, and K2CO3 in pyridine at 110 °C and structurally characterized by various spectroscopic techniques including NMR spectroscopy, IR spectroscopy, HRMS and elemental analysis studies. Complex 2b is also characterized by X-ray crystallography.

Accessing pyrrolo[1,2-a]indole derivatives via visible-light-induced dearomatizative cyclization of indoles.

Pyrrolo[1,2-a]indoles are structurally important scaffolds in many natural products and bioactive compounds. Herein, we report a novel synthetic method for pyrrolo[1,2-a]indole derivatives through visible-light-induced cascade dearomatizative cyclization of indoles with external nucleophiles. Moderate yields, good diastereoselectivities, and excellent regioselectivities were generally observed with the resultant indole-fused polycyclic compounds.

New cytotoxic indole derivatives with anti-FADU potential produced by the endophytic fungus Penicillium oxalicum 2021CDF-3 through the OSMAC strategy.

Fungi possess well-developed secondary metabolism pathways that are worthy of in-depth exploration. The One Strain Many Compounds (OSMAC) strategy is a useful method for exploring chemically diverse secondary metabolites. In this study, continued chemical investigations of the marine red algae-derived endophytic fungus Penicillium oxalicum 2021CDF-3 cultured in PDB media yielded six structurally diverse indole derivatives, including two new prenylated indole alkaloids asperinamide B (1) and peniochroloid B (5), as well as four related derivatives (compounds 2-4 and 6). The chemical structures of these compounds, including the absolute configurations of 1 and 5, were determined by extensive analyses of HRESIMS, 1D and 2D NMR spectroscopic data, and TDDFT-ECD calculations. Compound 1 was found to possess an unusual 3-pyrrolidone dimethylbenzopyran fused to the bicyclo[2.2.2]diazaoctane moiety, which was rare in previously reported prenylated indole alkaloids. In vitro cytotoxic experiments against four human tumor cell lines (HeLa, HepG2, FADU, and A549) indicated that 1 strongly inhibited the FADU cell line, with an IC50 value of 0.43 ± 0.03 μM. This study suggested that the new prenylated indole alkaloid 1 is a potential lead compound for anti-FADU drugs.

Rongalite induced metal-free C(sp2)-H functionalization of indoles: direct access to 3-(sulfonylmethyl) indoles.

A rongalite-induced C(sp2)-H functionalization reaction has been developed for the synthesis of 3-(phenylsulfonylmethyl) indole derivatives from indole and arylsulfonyl hydrazides. This regioselective C-H functionalization provides a wide range of C-3 sulfonylmethyl indoles with upto 90% yields. Here, rongalite functions as a C1 unit source and a single electron donor. The use of inexpensive rongalite (ca. $0.03 per 1 g), mild reaction conditions and gram-scale synthesis are some of the key features of this methodology.

Recent development in the synthesis of imidazo[1,5-a]indole derivatives: an in-depth overview.

In the realm of nitrogen-fused heterocycles, imidazo[1,5-a]indole and its derivatives are recognized as privileged structural patterns in various pharmaceutical drugs and biologically active natural products, emphasizing their significance. This review comprehensively explores the synthetic strategies for constructing imidazo[1,5-a]indole scaffolds, with a particular focus on transition metal-catalyzed methodologies. The primary highlighted method is [4 + 1] annulation, along with other notable approaches such as C-H activation/cyclization, enantioselective C-H annulation, intramolecular hydroamination, and double cyclization processes.

T-BuOLi promoted regioselective N-thiolation of indoles with N-arylthio phthalimide.

The selective N-thiolation of indole substrates poses a challenge due to their diminished nucleophilicity at nitrogen. Herein, we present a novel method for the thiolation of the NH group in indole derivatives by using N-arylthio phthalimide as the sulfur source, t-BuOLi as the base and MeCN as the solvent. The process was successfully conducted under transition metal catalyst-free and room temperature conditions with a high product yield and a short reaction time. The developed protocol exhibited excellent regioselectivity and broad substrate tolerance in the preparation of N-thioindoles with diverse functional groups.