Indole Framework Research Articles

Palladium-Catalyzed Direct and Specific C-7 Acylation of Indolines with 1,2-Diketones

The indole scaffold is a ubiquitous and useful substructure, and extensive investigations have been conducted to construct the indole framework and/or realize indole modification. Nevertheless, the direct selective functionalization on the benzenoid core must overcome the high activity of the C-3 position and still remains highly challenging. Herein, a palladium-catalyzed direct and specific C-7 acylation of indolines in the presence of an easily removed directing group was developed. This strategy usually is considered as a practical strategy for the preparation of acylated indoles because indoline can be easily converted to indole under oxidation conditions. In particular, our strategy greatly improved the alkacylation yield of indolines for which only an unsatisfactory yield could be achieved in the previous studies. Furthermore, the reaction can be scaled up to gram level in the standard reaction conditions with a much lower palladium loading (1 mol %).

The C-H functionalization of N-alkoxycarbamoyl indoles by transition metal catalysis.

Indole and its congeners are ubiquitous nitrogen-containing organic scaffolds present in a plethora of natural products, marketed drugs, and other organic functional molecules. Recent years have witnessed tremendous advances in the diversification of this motif and its biological applications via transition-metal-catalyzed auxiliary assisted site-selective inert C-H functionalization. In this burgeoning field, N-methoxy/ethoxy/pivaloxy amide functionality has emerged as a most potent auxiliary/DG (directing group) for a wide range of C-C and C-heteroatom bond formations, providing a new advance for forging structurally fabricated polycyclic indole frameworks. This review aims to highlight evolved transformations, like arylation, alkylation, alkenylation, allylation, amidation, difluorovinylation, deuteration, hydroarylation, etc., and the applications of N-alkoxycarbamoyl indole derivatives made within the period of 2014-August 2021. Additionally, explicit mechanistic underpinnings have also been provided in the appropriate places.

FeCl3 catalyzed intermolecular reaction between enol ethers and anilines: Access to 2,3-substituted indoles through aryl group migration

An intermolecular FeCl3 catalyzed reaction between anilines and enol ethers is described. A variety of enol ethers and aromatic amines undergo a CC bond formation followed by cyclization via CN bond formation to afford the 2,3-disubstituted indoles, involving an unexpected aryl group migration. In this methodology, anilines act as bis-nucleophiles, wherein the initial attack occurs at the α-position of enol ether from the ortho position of aniline followed by the subsequent reaction of the amine moiety of aniline at the β-position, leading to the indole framework. This method is simple, obviates the use of expensive/hazardous transition-metal catalysts, and offers a wide range of substrate scope.

Collective Total Synthesis of Aspidofractinine Alkaloids through the Development of a Bischler–Napieralski/Semipinacol Rearrangement Reaction

AbstractA tandem Bischler–Napieralski/semipinacol rearrangement reaction has been developed for the purpose of assembling a bis(spirocyclic) indole framework, a privileged structural unit of aspidofractinine‐type monoterpenoid indole alkaloids, and was used in combination with a subsequent Mannich reaction to expeditiously construct the central bridged bicyclo[2.2.1]heptane ring system of these molecules with contiguous quaternary centers. The development of this novel strategy culminated in the collective total synthesis of four aspidofractinine alkaloids.

Collective Total Synthesis of Aspidofractinine Alkaloids through the Development of a Bischler-Napieralski/Semipinacol Rearrangement Reaction.

A tandem Bischler-Napieralski/semipinacol rearrangement reaction has been developed for the purpose of assembling a bis(spirocyclic) indole framework, a privileged structural unit of aspidofractinine-type monoterpenoid indole alkaloids, and was used in combination with a subsequent Mannich reaction to expeditiously construct the central bridged bicyclo[2.2.1]heptane ring system of these molecules with contiguous quaternary centers. The development of this novel strategy culminated in the collective total synthesis of four aspidofractinine alkaloids.

Indole Derivatives as Anti-Tubercular Agents: An Overview on their Synthesis and Biological Activities.

The indole framework is considered as one of the privileged structures in the area of medicinal chemistry and drug discovery because compounds containing this framework have shown to possess a remarkable ability to bind with many receptors or proteins with high affinity. It is therefore not surprising that the indole nucleus is a frequently found moiety in many bioactive agents or drugs. Indole derivatives have also been explored or studied for their anti-tubercular properties for a long time. The growth inhibition of Mycobacterium tuberculosis (MTB) in vitro and in vivo by the gut microbiota metabolite indole propionic acid (IPA) is one of the recent examples. Notably, tuberculosis (TB), an intractable disease and a major cause of death worldwide, has caused an alarming rise in the number of TB cases recently because of two main reasons, i.e., a several-fold rise among HIV-infected patients and increased drug resistance by some bacterial strains. Thus, the identification of new agents or potential drugs against TB is urgently needed. While the specific pharmacological target or mechanism of action (MOA) for antitubercular activities has been reported for many indole derivatives, the MOA is not well defined or known for a number of indole derivatives though they were found to be active against MTB. In the current review article, we have focused on both types of indole derivatives that have shown activities against MTB. The indoles with known MOA are further segregated based on this pharmacological target reported or indicated whereas other indoles are classified based on the type of anti-TB properties shown by them. The literature for the last 20 years as well as related to up to date knowledge and information was searched on Pubmed, Google Scholar, MEDLINE, and various other databases until August 2020. A diverse range of functionalized indole derivatives, such as indole-based alkaloids, simple indoles, fused indoles, amide/peptide derivatives of indole, isatin derivatives, etc., have been reported to possess anti-tubercular activities. The anti-tubercular activities, in silico studies (if reported) and the chemical syntheses (in most of the cases) of representative indole derivatives are presented briefly in the current article. The papers referenced by this review allow a deep analysis of the status of the indole-based anti-tubercular agents explored over the past two decades. This review aims at stimulating renewed interest and effort in the discovery and development of new indole-based agents or potential drugs for the treatment of TB. The emergence of modern methods, especially those based on transition metal-catalyzed reactions, has opened up tremendous opportunities in the area of indole synthesis. The desired goal would be to have utilized these modern methodologies for the identification of potent and promising agents to fight against MTB.

Alkaloid constituents from the fruits of Flueggea virosa.

Three new indole alkaloids, flueindolines A-C (1-3), along with nine known alkaloids (4-12), were isolated from the fruits of Flueggea virosa (Roxb. ex Willd.) Voigt. Compounds 1 and 2 are two new fused tricyclic indole alkaloids possessing an unusual pyrido[1, 2-a]indole framework, and 3 presents a rare spiro (pyrrolizidinyl-oxindole) backbone. Their structures with absolute configurations were elucidated by means of comprehensive spectroscopic analysis, chemical calculation, as well as X-ray crystallography. Chiral resolution and absolute configuration determination of the known compounds 4, 10, and 11 were reported for the first time. The hypothetical biogenetical pathways of 1-3 were herein also proposed.

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole-Indole Conjugates as Anticancer CDK Inhibitors.

On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.

An efficient method for the azocino[4,3-b]indole framework of strychnos alkaloids: DFT investigations on the electronic and spectroscopic properties

An efficient method for the azocino[4,3-b]indole framework of strychnos alkaloids: DFT investigations on the electronic and spectroscopic properties

Carbene-catalyzed asymmetric Friedel\u2013Crafts alkylation-annulation sequence and rapid synthesis of indole-fused polycyclic alkaloids

Organocatalyzed asymmetric Friedel–Craft reactions have enabled the rapid construction of chiral molecules with highly enantioselectivity enriching the toolbox of chemists for producing complex substances. Here, we report N-heterocyclic carbene-catalyzed asymmetric indole Friedel–Crafts alkylation-annulation with α,β-unsaturated acyl azolium as the key intermediate, affording a large variety of indole-fused polycyclic alkaloids with excellent diastereo- and enantioselectivities. The reaction mechanism is also investigated, and the reaction products can be easily converted to highly functionalized indole frameworks with different core structures.

Unusual Formation of Cyclopenta[ b]indoles from 3-Indolylmethanols and Alkynes.

Acid-promoted synthesis of cyclopenta[ b]indole frameworks from 3-indolylmethanols and alkynes has been reported. The overall transformation represents a formal [3 + 2] annulation via rearrangement. This protocol showed good generality for the carbinol substrates as well as alkynes and allowed the generation of structurally diverse cyclopenta[ b]indoles. Terminal alkynes, dialkyl-substituted internal alkynes, and alkynes with electron-deficient substituents were found to be not suitable for this transformation. Similarly, N-Ts and N-Boc groups were compatible with reaction conditions, whereas N-Ac and N-Tf failed to undergo this reaction. Isolation of vinyl chloride intermediate suggested the involvement of a vinylic carbocation intermediate. A mechanism has been proposed involving a ring-opening-ring-closing cascade followed by a 1,3-indole migration process via a spirocyclobutene intermediate.

Copper‐Catalyzed Sequential C(sp2)/C(sp3)−H Amination of 2‐Vinylanilines with N‐Fluorobenzenesulfonimide

AbstractAn oxidative C−H diamination of 2‐vinylanilines with N‐fluorobenzenesulfonimide (NFSI) was developed for the efficient synthesis of indole frameworks. The reaction proceeded via sequential intra‐/intermolecular diamination of C(sp2)−H and C(sp3)−H bond, incorporating one nitrogen from the substrate and the other nitrogen from the NFSI.magnified image

Efficient biosynthesis of heterodimeric C3-aryl pyrroloindoline alkaloids

Many natural products contain the hexahydropyrrolo[2, 3-b]indole (HPI) framework. HPI containing chemicals exhibit various biological activities and distinguishable structural arrangement. This structural complexity renders chemical synthesis very challenging. Here, through investigating the biosynthesis of a naturally occurring C3-aryl HPI, naseseazine C (NAS-C), we identify a P450 enzyme (NascB) and reveal that NascB catalyzes a radical cascade reaction to form intramolecular and intermolecular carbon–carbon bonds with both regio- and stereo-specificity. Surprisingly, the limited freedom is allowed in specificity to generate four types of C3-aryl HPI scaffolds, and two of them were not previously observed. By incorporating NascB into an engineered strain of E. coli, we develop a whole-cell biocatalysis system for efficient production of NAS-C and 30 NAS analogs. Interestingly, we find that some of these analogs exhibit potent neuroprotective properties. Thus, our biocatalytic methodology offers an efficient and simple route to generate difficult HPI framework containing chemicals.

Synthetic Methods for 3,4‐Fused Tricyclic Indoles via Indole Ring Formation

Abstract3,4‐Fused tricyclic indole frameworks are found in various bioactive natural products and pharmaceuticals. The development of an efficient synthetic method for this structural motif has therefore attracted attention in the field of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent advances in the synthesis of 3,4‐fused tricyclic indoles. This class of synthetic methods can be roughly classified into two categories: methods using functionalized indole derivatives as starting materials to construct a fused medium‐sized ring (Types A–D: Category I), and methods of constructing a 3,4‐fused tricyclic indole skeleton via indole ring formation (Types E–G: Category II). In this focus review, synthetic methods for 3,4‐fused tricyclic indoles classified as Category II methods are highlighted, following a brief overview of the Category I methods.

Acetylenic Indole‐Encapsulated Schiff Bases: Synthesis, In Silico Studies as Potent Antimicrobial Agents, Cytotoxic Evaluation and Synergistic Effects

AbstractA family of pharmacophore acetylenic indole‐3‐carboxaldehyde (3) and acetylenic indole schiff bases (5 a‐5 i) bearing indole framework were synthesized to afford structurally diverse moieties. Acetylenic indole‐3‐carboxaldehyde was coupled with various amines to furnish the novel scaffolds 5 a‐5 i. These acetylenic indole Schiff bases (AISB) were synthesized in shorter times under microwave irradiation in comparison to classical reaction conditions. AISB were experimentally characterized by using IR, 1H NMR, 13C NMR, X ray crystallographic and mass spectrometric methods. The synthesized compounds showed promising anti‐bacterial and anti‐fungal properties when tested in vitro against six bacterial and seven fungal strains. Among these, hybrids 5 a, 5 c, 5 e and 5 g were found to be even more potent than the standard drugs and were more influential against the bacterial than the fungal strains. These more potent compounds were then evaluated for their cytotoxicity by MTT assay on Hek293 and HeLa cells. The synergistic effect of bis‐acetylenic compound 5 g with kanamycin and amphotericin B has also been scrutinized. Further, the structural and electronic properties of the molecules were investigated theoretically by performing density functional theory (DFT).

Weak Directing Group Steered Formal Oxidative [2+2+2]-Cyclization for Selective Benzannulation of Indoles.

A double C-H activation and double insertion process to achieve the synthesis benzo[e]indole frameworks has been disclosed. This type of benzannulation is directed by a trifluoromethylketone moiety, which is easy to install on the indole C3-position. Overall the reaction takes places as an oxidative cyclization of two alkynes with the C4-C5 position of indole.

Design of C3‐Alkenyl‐Substituted 2‐Indolylmethanols for Catalytic Asymmetric Interrupted Nazarov‐Type Cyclization

AbstractThe C3‐alkenyl‐substituted 2‐indolylmethanols have been designed as a new class of substrates for catalytic asymmetric interrupted Nazarov‐type cyclizations. In the presence of chiral phosphoric acid as a mild chiral Brønsted acid, the interrupted Nazarov‐type cyclization of C3‐alkenyl‐substituted 2‐indolylmethanols with nucleophiles occurred smoothly to construct cyclopenta[b]indole frameworks in generally excellent diastereo‐ and enantioselectivities (up to >95:5 dr, >99% ee).magnified image

Diastereo- and enantioselective construction of chiral cyclopenta[b]indole framework via a catalytic asymmetric tandem cyclization of 2-indolymethanols with 2-naphthols

The title reaction has been established in the presence of chiral phosphoric acids, which constructed chiral cyclopenta[b]indole frameworks in high stereoselectivities.

Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2α and Its Paralog CK2α′

Protein kinase CK2, a member of the eukaryotic protein kinase superfamily, is associated with cancer and other human pathologies and thus an attractive drug target. The indeno[1,2-b]indole scaffold is a novel lead structure to develop ATP-competitive CK2 inhibitors. Some indeno[1,2-b]indole-based CK2 inhibitors additionally obstruct ABCG2, an ABC half transporter overexpressed in breast cancer and co-responsible for drug efflux and resistance. Comprehensive derivatization studies revealed substitutions of the indeno[1,2-b]indole framework that boost either the CK2 or the ABCG2 selectivity or even support the dual inhibition potential. The best indeno[1,2-b]indole-based CK2 inhibitor described yet (IC50 = 25 nM) is 5-isopropyl-4-(3-methylbut-2-enyl-oxy)-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (4p). Herein, we demonstrate the membrane permeability of 4p and describe co-crystal structures of 4p with CK2α and CK2α′, the paralogs of human CK2 catalytic subunit. As expected, 4p occupies the narrow, hydrophobic ATP site of CK2α/CK2α′, but surprisingly with a unique orientation: its hydrophobic substituents point towards the solvent while its two oxo groups are hydrogen-bonded to a hidden water molecule. An equivalent water molecule was found in many CK2α structures, but never as a critical mediator of ligand binding. This unexpected binding mode is independent of the interdomain hinge/helix αD region conformation and of the salt content in the crystallization medium.

Recent Progress in Biological Activities of Indole and Indole Alkaloids.

The indole scaffold is found in a wide range of bioactive heterocycles and natural products. Moreover, the indole moiety is considered as the active principle in several alkaloids such as mitomycin C and reserpine. Thus, over the past decade, chemists are increasingly attracted towards the studies on the pharmacological and therapeutic activities of indole containing compounds. Furthermore, the molecular structures of well-known drugs such as sumatriptan, tadalafil, fluvastatin and rizatriptan are based on indole frameworks. This mini-review covers some of the significant and recent achievements of indole derivatives with respect to their biological activities up to 2015.