Indole Moiety Research Articles

Synthesis and Anticancer Activity of Indole-Functionalized Derivatives of Betulin.

Pentacyclic triterpenes, including betulin, are widespread natural products with various pharmacological effects. These compounds are the starting material for the synthesis of substances with promising anticancer activity. The chemical modification of the betulin scaffold that was carried out as part of the research consisted of introducing the indole moiety at the C-28 position. The synthesized new 28-indole-betulin derivatives were evaluated for anticancer activity against seven human cancer lines (A549, MDA-MB-231, MCF-7, DLD-1, HT-29, A375, and C32). It was observed that MCF-7 breast cancer cells were most sensitive to the action of the 28-indole-betulin derivatives. The study shows that the lup-20(29)-ene-3-ol-28-yl 2-(1H-indol-3-yl)acetate caused the MCF-7 cells to arrest in the G1 phase, preventing the cells from entering the S phase. The performed cytometric analysis of DNA fragmentation indicates that the mechanism of EB355A action on the MCF-7 cell line is related to the induction of apoptosis. An in silico ADMET profile analysis of EB355A and EB365 showed that both compounds are bioactive molecules characterized by good intestinal absorption. In addition, the in silico studies indicate that the 28-indole-betulin derivatives are substances of relatively low toxicity.

Indole Fused Benzimidazole Hybrids: A Promising Combination to Fulfill Pharmacological Significance

Heterocyclic compounds are an essential part of drug design and discovery. The pharmaceutical industry uses and investigates nitrogen-containing heterocycles because they are crucial in discovering and developing novel therapeutic compounds. Due to their diverse pharmacological potentials, benzimidazole derivatives have been widely useful in medicinal chemistry over the past few decades. Similarly, indole derivatives also possess a wide range of biological potential. It is observed that compounds incorporating two or more structural moieties in a single hybrid structure are always known to have a wide range of pharmacological activities. Thus, the pharmacological properties of benzimidazole scaffolds can be improved by incorporating indole moieties. The present review demonstrates the recent development in pharmacology and structure-activity relationships of indole-benzimidazole hybrid derivatives. It may help researchers and computational chemists to find the lead structures associated with indole-benzimidazole in drug discovery and design.

Potent and biostable inhibitors of the main protease of SARS-CoV-2

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection invitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

Mechanistic Insights into Cobalt-Catalyzed Regioselective C4-Alkenylation of 3-Acetylindole: A Detailed Theoretical Study.

A detailed mechanistic study of Co(III)-catalyzed C4-alkenylation of 3-acetylindole (1a) was done based on calculations at density functional theory (DFT) and correlated wave function levels. The whole catalytic cycle consists of four steps: C-H activation, olefin insertion, β-hydride elimination, and regeneration of the catalyst. The theoretical results support olefin insertion as the rate-determining step leading to the experimentally observed regioselectivity of the C4 site over the C2 site. By the analysis of three-dimensional (3D) geometries and the NCl plot, the preference for the C4 site over the C2 site could be attributed to the weaker repulsive interaction between the indole moiety and olefin in the transition states of the olefin insertion step for the former. The reliability of the theoretical mechanistic results is further confirmed through the DFT calculation of other related indole derivatives and olefin substrates.

The Biosynthesis Related Enzyme, Structure Diversity and Bioactivity Abundance of Indole-Diterpenes: A Review.

Indole diterpenes are a large class of secondary metabolites produced by fungi, possessing a cyclic diterpenoid backbone and an indole moiety. Novel structures and important biological activity have made indole diterpenes one of the focuses of synthetic chemists. Although the discovery, identification, structural diversity, biological activity and especially structure–activity relationship of indole diterpenes have been reported in some papers in recent years, they are absent of a systematic and comprehensive analysis, and there is no elucidation of enzymes related to this kind of natural product. Therefore, it is necessary to summarize the relevant reports to provide new perspectives for the following research. In this review, for the first time, the function of related synthases and the structure–activity relationship of indole diterpenes are expounded, and the recent research advances of them are emphasized.

Arylation and Aryne Insertion into C-Acylimines: A Simple, Flexible, and Divergent Synthesis of C2-Aryl Indoles.

We reveal a direct strategy for the flexible synthesis of C2-aryl/heteroaryl indoles without transition metal catalysts. The synthesis involves a one-pot, four-component reaction of readily available starting materials to offer diversity around the indole moiety with a broad substrate scope and high yields. The reaction proceeds via the Friedel-Crafts C-arylation of C-acylimine formed in situ, followed by N-arylation with aryne, a formal [3+2] cycloaddition, and a subsequent aromatization cascade.

Formal Syntheses of Dictyodendrins B, C, and E by a Multi-Substituted Indole Synthesis

AbstractThe dictyodendrins are a family of marine alkaloids, which possess a highly substituted pyrrolo[2,3-c]carbazole core. This core structure can be regarded as a multi-substituted indole and aniline moiety. To achieve a concise synthesis of dictyodendrins, we planned to capitalize on our previously developed multi-substituted indole synthesis. By using this method along with two C–H functionalizations, formal syntheses of dictyodendrins B, C, and E were achieved.

Recent Advances in the Catalytic Asymmetric Friedel-Crafts Reactions of Indoles.

Functionalized chiral indole derivatives are privileged and versatile organic frameworks encountered in numerous pharmaceutically active agents and biologically active natural products. The catalytic asymmetric Friedel–Crafts reaction of indoles, catalyzed by chiral metal complexes or chiral organocatalysts, is one of the most powerful and atom-economical approaches to access optically active indole derivatives. Consequently, a wide range of electrophilic partners including α,β-unsaturated ketones, esters, amides, imines, β,γ-unsaturated α-keto- and α-ketiminoesters, ketimines, nitroalkenes, and many others have been successfully employed to achieve a plethora of functionalized chiral indole moieties. In particular, strategies for C–H functionalization in the phenyl of indoles require incorporation of a directing or blocking group in the phenyl or azole ring of indole. The discovery of chiral catalysts which can control enantiodiscrimination has gained a great deal of attention in recent years. This review will provide an updated account on the application of the asymmetric Friedel–Crafts reaction of indoles in the synthesis of diverse chiral indole derivatives, covering the timeframe from 2011 to today.

Inhibition of Cholinesterases by Benzothiazolone Derivatives

Thirteen benzothiazolone derivatives (M1–M13) were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs) and monoamine oxidases (MAOs). All the compounds inhibited ChEs more effectively than MAOs. In addition, most of the compounds showed higher inhibitory activities against butyrylcholinesterase (BChE) than acetylcholinesterase (AChE). Compound M13 most potently inhibited BChE with an IC50 value of 1.21 μM, followed by M2 (IC50 = 1.38 μM). Compound M2 had a higher selectivity index (SI) value for BChE over AChE (28.99) than M13 (4.16). The 6-methoxy indole group of M13 was expected to have a greater effect on BChE inhibitory activity than the other groups. Kinetics and reversibility tests showed that M13 was a reversible noncompetitive BChE inhibitor with a Ki value of 1.14 ± 0.21 μM. In a docking simulation, M13 is predicted to form a hydrogen bond with the backbone carbonyl group of Ser287 of BChE through its methoxy indole moiety and π−π interactions between its benzothiazolone group and the side chain of Trp82 with the five-membered pyrrole ring and with the six-membered benzene ring. From these results, it is suggested that M13 is a BChE inhibitor and a potential candidate agent for the treatment of Alzheimer’s disease.

A New Family of Indolyl‐type Benzimidazolium Salts Applied in Suzuki‐Miyaura Coupling of Aryl Chlorides

AbstractA new class of indolyl‐based benzimidazolium salts has first been obtained by a simple process from commercially available indole, 4‐iodoanisole, and benzimidazole. The structure of these salts offers beneficial features which include the high potential of steric and electronic tunability on the indole moiety and that of steric effect on the wingtip of benzimidazole moiety. The combination of indolyl‐based benzimidazolium salts and palladium metal precursors formed in situ are high‐efficient catalysts for accessing a wide range of biaryls in good to excellent yields, in particular, di‐ortho‐substituted biaryls, as well as good functional group tolerance, and the catalyst loading down to 0.25 mol % of Pd can be achieved.

Organocatalytic Atroposelective Synthesis of Indole Derivatives Bearing Axial Chirality: Strategies and Applications.

Catalytic atroposelective syntheses of axially chiral compounds have stimulated extensive interest in multiple communities, such as synthetic chemistry, biochemistry, and materials science, because of the intriguing characteristics of atropisomerism. In particular, atropisomeric indole derivatives, which contain a kind of five-membered heterocyclic framework, are widely distributed in a number of natural alkaloids, biologically relevant compounds, chiral ligands, and chiral organocatalysts. Hence, the catalytic atroposelective synthesis of indole derivatives bearing axial chirality is of considerable importance and has become an emerging focus of research. However, there are substantial challenges associated with the atroposelective synthesis of indole derivatives, including remote ortho-substituents around the chiral axis, a lower barrier for rotation, and a weaker configurational stability than that of atropisomeric six-membered biaryls. Therefore, the development of effective strategies toward the catalytic atroposelective synthesis of indole derivatives has become an urgent task.In order to tackle these challenges and to accomplish the task, our group devised a unique strategy of designing indole-derived platform molecules and developing organocatalytic enantioselective transformations of such platform molecules to synthesize atropisomeric indole derivatives; asymmetric organocatalysis has tremendous advantages and was the research area recognized by the Nobel Prize in Chemistry in 2021. This Account summarizes our endeavors in the organocatalytic atroposelective synthesis of indole derivatives bearing axial chirality. In brief, we devised and developed a series of indole-derived platform molecules, such as indolylmethanols, (hetero)aryl indoles, oxindole-based styrenes, N-aminoindoles, and indole-based homophthalic anhydrides, by introducing different functional groups onto the indole ring to achieve new reactivity and modulate the reactive site of the indole ring. As a result, these indole-derived platform molecules possess versatile and unique reactivity and are capable of undergoing a variety of organocatalytic enantioselective transformations for preparing structurally diversified indole derivatives with axial chirality.We used these strategies to accomplish the atroposelective synthesis of plenty of indole derivatives with axial chirality, including (hetero)aryl indoles, alkene-indoles, oxindole-based styrenes, N-pyrrolylindoles, and isochromenone-indoles. In addition, we gave a thorough and detailed understanding of the designed reaction by investigating the reaction pathway and activation mode. More importantly, we studied the biological activity of some products and performed catalyst design on the basis of atropisomeric indole moieties, which are helpful for disclosing more applications of indole derivatives bearing axial chirality.In the future, the organocatalytic atroposelective synthesis of indole derivatives bearing axial chirality will indubitably remain a frontier topic in the research area of asymmetric catalysis and chiral indole chemistry despite challenging issues, for instance, the atroposelective synthesis of novel indole derivatives bearing an unconventional chiral axis, the development of atropisomeric indole derivatives into powerful catalysts or ligands, and the discovery of atroposelective indole derivatives as potent drug candidates. We hope our efforts summarized in this Account will encourage chemists worldwide to devise innovative strategies toward solving the challenging issues that remain in this field, thus promoting its development to a higher level.

Construction of Spiropyrroloindolines by Dearomative [3+2]-Cycloaddition of Indoles with Oxindole-Embedded Azaoxyallyl ­Cations

AbstractA dearomative [3+2]-cycloaddition reaction of oxindole-embedded azaoxyallyl cations with indoles at the C3 position has been developed. The use of this new class of azaoxyallyl cation species in the reaction permits access to more-elaborate hexahydropyrrolo[2,3-b]indole moieties that contain a spiro-oxindole ring. The transformation displays a broad substrate scope and good regio- and stereoselectivity for the cycloaddition step. Several observations suggested that this class of azaoxyallyl cations can display a different reactivity pattern from those of commonly employed azaoxyallyl cation systems.

GREEN SYNTHESIS OF NEW HYDRAZONE DERIVATIVES

Novel set of hippuric hydrazones (6-9) bearing indole and quinoline moieties were synthesized in three steps following the protocol of microwave irradiation and solvent-free conditions. The first series were synthesized by irradiate ethyl hippurate (3) with 1H-indole-6-carbaldehyde (4) under solvent-free conditions. The second series were synthesized by irradiate ethyl hippurate (3) with substituted 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (5) under solventfree conditions. This work aims to develop new synthetic route of hippuric hydrazones which may possess a promising biological activities against covid-19. The formation of the prepared heteroaromatic hydrazones were approved by spectral 1H NMR, IR and mass data

Synthesis of benzo[4,5]imidazo[1,2‐a]indolo[1,2‐c]quinazolines from 2‐(2‐bromoaryl)indoles and 2‐methoxybenzimidazoles under recyclable magnetic MOF‐199 catalysis

2‐(2‐Bromoaryl)indoles react with 2‐methoxybenzimidazoles in DMF in the presence of a catalytic amount of recyclable Fe3O4@SiO2@MOF‐199 along with K2CO3 to afford a series of benzo[4,5]imidazo[1,2‐a]indolo[1,2‐c]quinazolines in good yields. The reaction applies to a broad scope of 2‐(2‐bromoaryl)indoles containing electron‐donating or ‐withdrawing substituents on bromophenyl and indole moieties, and alkyl substituents at 3‐position of indole moiety. A reaction pathway involving a copper‐catalyzed Ullmann‐type C (sp2)‐N coupling and an addition‐elimination nucleophilic aromatic substitution via Meisenheimer complex followed by cyclocondensation is proposed for this catalytic process. The Fe3O4@SiO2@MOF‐199 catalyst could be recovered and reused several times without any change of catalytic activity.

Searching Potential Molecules Against SARS-CoV-2 from Costus arabicus L. Root Smoke: A Docking Study

Background: The root smoke of Costus arabicus L. (Qust-e Shirin) has been used in Iranian traditional medicine (ITM) for rhinorrhea and catarrh, especially with infectious origin. Objectives: This study aimed to inspect potential anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activities of chemical compositions of this smoke through a docking study. Materials and Methods: Based on our previous study on the chemical compositions of C. arabicus root smoke, the chemical structure of components was revealed by GC-MS. In this study, these structures were generated in HyperChem software, and an energy-minimization procedure was performed for the molecules. For the docking study, the Hex software was used. Docking was performed using the Protein Data Bank (PDB) structure of the COVID-19 RNA-dependent RNA polymerase (RdRp) (PDB ID: 6M71) enzyme which was obtained from PDB bank, water molecules were removed, Coleman charge was added, and non-polar hydrogens were merged. Then, docking was performed. Results: The result indicated the energy of each interaction between molecules and enzymes. The lower the energy, the higher the probability of interaction will be. The best molecule was 6H-quindoline which has the best total energy among the molecules. The next molecule was 5-methoxy-alpha methyl tryptamine with -210.82 kcal energy. Their similar structure in indole moiety suggests that this fragment can play a crucial role in attachment to the enzyme and can be kept intact in future designs against COVID-19 inhibitors. Conclusion: In conclusion, this study showed that C. arabicus root smoke may be effective in SARS-CoV-2 infection. Further in vitro and in vivo studies on the activity of the smoke and its constituents against COVID-19 would be fruitful.

Enhancing the biological properties of zinc complexes with bis(indolyl)methane groups: Synthesis, characterization, DNA interaction, and biocide activity

The unprecedented mononucleated ligand (6,6-di(1H-indol-3-yl)-N,N-bis(pyridin-2-ylmethyl)hexan-1-amine (LC5) with an N3-donor set and its complexes [Zn(LC5)Cl2] • 2CH3OH (1) and [Zn(LC5)2](ClO4)2 (2), were successfully prepared. All compounds were fully characterized by a suite of physicochemical methods. Fluid 1H and 13C NMR spectroscopy, as well as DFT and TD-DFT calculations, were carried out to propose a viable structural arrangement for both complexes. The interaction between these compounds and DNA was monitored in the UV region where binding constants (Kb) were estimated (2 > 1 > LC5). These data were corroborated by DNA cleavage assays using groove binders, circular dichroism, and docking studies. Both complexes confirmed their biocide activity against selected microorganisms: Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria, the filamentous fungi A. fumigatus and S. cerevisiae. Finally, the cytotoxic activities of 1 and 2 were tested against the erythroleukemia K562 cell line. For all biological studies, it was probed that the presence of the indole moieties and the zinc atoms in the chemical composition of the complexes studied could increase the magnitude of the activity following the order: 2 > 1 > LC5, where a linear relationship between the biological activity upon K562 cells (IC50) and DNA binding studies (Kb) was found.

New-Generation Heterocyclic Bis-Pentamethinium Salts as Potential Cytostatic Drugs with Dual IL-6R and Mitochondria-Targeting Activity.

IL-6 signaling is involved in the pathogenesis of a number of serious diseases, including chronic inflammation and cancer. Targeting of IL-6 receptor (IL-6R) by small molecules is therefore an intensively studied strategy in cancer treatment. We describe the design, synthesis, and characteristics of two new bis-pentamethinium salts 5 and 6 (meta and para) bearing indole moieties. Molecular docking studies showed that both compounds have the potential to bind IL-6R (free energy of binding −9.5 and −8.1 kcal/mol). The interaction with IL-6R was confirmed using microscale thermophoresis analyses, which revealed that both compounds had strong affinity for the IL-6R (experimentally determined dissociation constants 26.5 ± 2.5 nM and 304 ± 27.6 nM, respectively). In addition, both compounds were cytotoxic for a broad spectrum of cancer cell lines in micromolar concentrations, most likely due to their accumulation in mitochondria and inhibition of mitochondrial respiration. In summary, the structure motif of bis-pentamethinium salts represents a promising starting point for the design of novel multitargeting compounds with the potential to inhibit IL-6 signaling and simultaneously target mitochondrial metabolism in cancer cells.

Total Synthesis of Melicoptelines C-E: Antiviral Cyclopeptides Containing a Hexahydropyrrolo[2,3-b]indole Moiety.

Melicoptelines, natural cyclopeptides containing a 3a-hydroxy hexahydropyrrolo[2,3-b]indole (HPI) moiety, exhibit anti-influenza activity. Herein, we report the first total synthesis of melicoptelines C-E (1-3, respectively). The core 3a-hydroxy HPIs were synthesized in a diastereoselective manner from l-tryptophan using dimethyldioxirane-mediated oxidation. Subsequently, sequential peptide couplings and cyclization completed the synthesis of melicoptelines C-E and unnatural melicopteline 4. The synthesized melicoptelines were evaluated for their anti-influenza activity, and melicopteline E showed the most potent inhibition of cytopathic effects.

7,12‐Dihydrobenzo[de]indolo[3,2‐b]quinoline: Unique Reactivity and Redox Interconversion

AbstractAcetyl‐substituted 7,12‐dihydrobenzo[de]indolo[3,2‐b]quinoline was developed as a N‐substituted polycyclic heteroaromatic molecule via Pd‐catalyzed cyclo‐isomerization of an alkyne precursor, followed by intramolecular Goldberg amination. This compound showed unique reactivity, notably, base‐mediated deacylative oxygenation and photo‐Fries rearrangement. A series of products exhibited characteristic electronic properties based on the redox state of the corresponding nitrogen atoms. The photo‐rearranged product, which possesses a 1,2‐diaminoethene substructure, akin to the redox functionality of the natural flavin adenine dinucleotide, underwent reversible interconversion with the corresponding oxidized form. The efficient stabilization of the highly electron‐rich 7,12‐dihydrobenzo[de]indolo[3,2‐b]quinoline skeleton was ascribed to the electron‐withdrawing effect, intramolecular hydrogen bonding of the acetyl group, and local aromatic stabilization in the indole moiety.

Cytochrome P450BltEnables Versatile Peptide Cyclisation to Generate Histidine‐ and Tyrosine‐Containing Crosslinked Tripeptide Building Blocks

AbstractWe report our investigation of the utility of peptide crosslinking cytochrome P450 enzymes from biarylitide biosynthesis to generate a range of cyclic tripeptides from simple synthons. The crosslinked tripeptides produced by this P450 include both tyrosine‐histidine (A−N−B) and tyrosine‐tryptophan (A−O−B) crosslinked tripeptides, the latter a rare example of a phenolic crosslink to an indole moiety. Tripeptides are easily isolated following proteolytic removal of the leader peptide and can incorporate a wide range of amino acids in the residue inside the crosslinked tripeptide. Given the utility of peptide crosslinks in important natural products and the synthetic challenge that these can represent, P450 enzymes have the potential to play roles as important tools in the generation of high‐value cyclic tripeptides for incorporation in synthesis, which can be yet further diversified using selective chemical techniques through specific handles contained within these tripeptides.