Samarth Institute of Pharmacy, Belhe.
A large variety of bioactive natural products and molecules with significant therapeutic value include indoles, a functional group that is widely distributed in nature. The development of new techniques for the synthesis of indole core and site-specific indoles has consequently increased exponentially. Greener techniques that employ solid acid catalysts, ionic liquids, water as a solvent, microwave irradiation, and solvent-free nanoparticles are replacing conventional methods for the synthesis of indoles. Additionally, the substituted indoles have a wide range of uses. 3-The sulfur-substituted indole derivative phenylthioindole has attracted attention because of its possible biological activity and use as a synthesis intermediary in medicinal chemistry. By nucleophilically substituting thiophenol for 3-haloindole under basic circumstances, this work describes an effective synthesis pathway for 3-phenylthioindole. In polar aprotic solvents, the reaction proceeds smoothly and produces the required thioether with excellent purity and good yield. Spectroscopic methods such as NMR, IR, and mass spectrometry were used to characterize the produced chemical. This technique provides a useful way to create sulfur-functionalized indole frameworks for additional research in medicinal chemistry.
The presence of a phenylthio (-SPh) group at the third position of the indole ring distinguishes 3-phenylthioindole, an organic molecule that is a member of the family of indole derivatives. Because it confers distinct chemical and biological characteristics, this structural alteration is important in synthetic, materials, and medicinal chemistry. Organic synthesis scientists have long been influenced by the indole alkaloids, which include vincristine and lysergic acid. In recent years, there has been a surge in interest in creating novel techniques for indole synthesis. These novel techniques have been dispersed across the organic chemistry literature. We offer a categorization scheme for all indole syntheses in this evaluation. We are aware that the topic has been on organic chemists' thoughts for over a century as we get closer to classifying the methods for indole production. The synthesis of indole has been reviewed several times. One We knew, too, that there was much more to say than we have. The reduction of oxindoles to indoles and the conversion of indolines to indoles have only been slightly discussed. The vast body of research on altering already-existing indoles has not been discussed. Our goal has always been to be illustrative rather than all-inclusive. However, it is clear that any indole synthesis needs to align with one of the nine strategic approaches listed above. The global research effort is coordinated and unified by the network of scientific citations. We anticipate broad acceptance of the indole syntheses categorization system that we have proposed. It will be simple to learn about the background and current state of that indole manufacturing technique as authors will be able to classify their techniques as they create new approaches to the indole nucleus. We hope that efforts will then be focused on the very real obstacles that still need to be solved, in addition to preventing duplication. Notably, each of these nine techniques reported significant new contributions in 2009, the most recent year we have discussed. At the conclusion of each segment, we have indicated them. Given their diverse range of biological functions, indole derivatives have gained notable attention in recent years. The anticonvulsant medication design is predicated on the idea that at least one phenyl or comparable aromatic group near a two-electron donor atom is necessary for the activity in maximum electroshock seizure (MES) assessment. Pentylenetetrazole (PTZ) assessment requires an alkyl group near a two-electron donor atom in order to be active. Several strategies for the development of novel antipsychotics have started to provide additional tools for relieving the symptoms of schizophrenia. In recent years, the pharmaceutical industry and academia have shown significant interest in the development of novel antipsychotics characterized by interaction with less obvious receptors such as metabotropic glutamate receptors and tachykinin receptors. [Stefania B. et al; 2008] Of the several varieties of epilepsy, Lennox-Gastaut syndrome (LGS) is a childhood-onset epilepsy that causes a variety of seizures that hinder young children's intellectual development. Treatment resistance is frequently the primary issue with LGS seizures. Rufinamide, an antiepileptic medication with a 1,2,3-triazole ring, is one of the first-line orphan medications used to treat individuals with LGS seizures. Padmaja.
Fig. 1 An Illustration of The Innovative Green Chemical Processes Used to Synthesize Indole Derivatives.
Classical Methods of Indole Synthesis
1)Fischer Indole Synthesis
The Fischer indole synthesis is one of the pioneering methods used for constructing indole nuclei and remains a cornerstone in heterocyclic chemistry. Developed by Emil Fischer in the late 19th century, this transformation is notable for its operational simplicity, broad substrate scope, and the ability to introduce a variety of substituents on the indole framework. The process generally proceeds through the following stages
Formation of the Hydrazone:
Initially, an arylhydrazine reacts with a carbonyl compound (ketone or aldehyde) to form the corresponding hydrazone under mild conditions. This step is usually catalyzed by acid, which also aids in subsequent rearrangements.
Tautomerization and [3,3]-Sigma tropic Rearrangement:
Under the influence of acid, the hydrazone undergoes tautomerization, forming an enehydrazine intermediate. This intermediate then participates in a [3,3]-sigmatropic rearrangement (often referred to as the Fischer rearrangement), which is the key step that sets the stage for indole formation.
Cyclization and Aromatization:
The rearranged intermediate cyclizes intramolecularly to form a dihydroindole species. Subsequent deprotonation and further acid-catalyzed steps result in the aromatization of the ring, yielding the indole product.
2)Madelung Synthesis
The Madelung synthesis is an early and classical method for the construction of indole derivatives, notable for its straightforward intramolecular cyclization approach. First reported by Erich Madelung, this reaction transforms suitably substituted N-arylacetamides into indoles via strong base-induced cyclization. Despite its historical origins, the method has undergone refinements to improve its scope and efficiency and continues to provide a foundation for more advanced synthetic strategies. the reaction proceeds via the following stages:
Deprotonation:
The base deprotonates the benzylic position (the methyl group adjacent to the aromatic ring), generating a stabilized benzylic carbanion. This step is critical, as it sets up the nucleophilic attack on the carbonyl moiety.
Intramolecular Nucleophilic Attack:
The carbanion then undergoes an intramolecular nucleophilic attack on the amide carbonyl group, leading to the formation of a cyclic intermediate. This cyclization forms a new carbon–carbon bond between the benzylic carbon and the carbonyl carbon.
Cyclization and Rearrangement:
The intermediate subsequently undergoes proton shifts and subsequent rearomatization, which culminates in the elimination of a small molecule (often water or an equivalent) to yield the indole nucleus.
3)Bartoli Indole Synthesis
The Bartoli indole synthesis, named after its developer, represents a notable advancement in the efficient assembly of the indole framework. Distinguished by its ability to construct polysubstituted indoles under relatively mild conditions, the Bartoli reaction has become a valuable tool, particularly when sterically encumbered substrates or a high degree of substitution is required. The key stages of the mechanism are as follows:
Initial Nucleophilic Addition:
The process commences with the nucleophilic attack of a vinyl Grignard reagent on an ortho-substituted nitroarene. This addition reaction is facilitated by the electron-deficient nature of the nitroarene, which is further activated by the adjacent substituent in the ortho position.
Reductive Cyclization:
Following the initial addition, an intramolecular electron transfer and reductive cyclization occur. This step converts the intermediate into a dihydroindole derivative. The reaction proceeds without the need for an external catalyst, relying instead on the inherent reactivity of the organometallic reagent and the nitro group.
Aromatization:
Finally, oxidation and rearomatization steps furnish the fully aromatic indole core. These steps typically occur under the reaction conditions, although a work-up step that involves mild oxidants may sometimes be employed to complete the transformation.
4)Hemetsberger–Knittel Reaction
The Hemetsberger–Knittel reaction is an elegant, albeit less commonly employed, method for constructing the indole scaffold. This transformation involves the thermal or base-induced cyclization of azidoacrylate or related precursors into substituted indoles. It offers a unique approach to indole synthesis by proceeding through nitrene intermediates, distinguishing it from more classical methods. The proposed mechanism includes several key steps:
Formation of the Nitro Intermediate:
Thermal activation or basic conditions initiate the decomposition of the azide functionality, generating a nitrene species that is poised for further transformation.
Cyclization:
The nitrene intermediate undergoes an intramolecular electrophilic attack on the adjacent carbon–carbon double bond. This attack induces cyclization, forming a cyclic intermediate that contains a nascent C–N bond, critical for indole formation.
Rearomatization:
Subsequent proton shifts and rearrangements facilitate the rearomatization of the ring system. This final step yields the substituted indole nucleus with concomitant elimination of nitrogen as a byproduct.
5)Leimgruber–Batcho Synthesis
The Leimgruber–Batcho synthesis is a robust and versatile method for the preparation of indole derivatives that has gained popularity for its operational simplicity and functional group tolerance. This reaction provides an efficient route to highly substituted indoles, making it particularly attractive for applications in medicinal chemistry and natural product synthesis. The main steps include:
Formation of the Enamine Intermediate:
Initially, an o-nitrotoluene derivative is condensed with a suitable reagent, such as dimethylformamide dimethyl acetal (DMF-DMA), leading to the formation of an enamine. This step is crucial as it activates the aromatic ring toward subsequent cyclization.
Cyclization and Reduction:
The enamine intermediate then undergoes cyclization under acidic or mildly reducing conditions. Concomitant reduction of the nitro group and rearomatization of the intermediate occur, resulting in the formation of the indole nucleus.The transformation typically involves a tandem process where cyclization is followed immediately by dehydrogenation or reduction steps to yield a fully aromatic indole system.
Medicinal Uses of Indole Derivatives
indole-based compounds have occupied a central position in medicinal chemistry due to their versatile biological activities. Their inherent structural features allow for extensive modification, facilitating the design of molecules that target a wide range of diseases.
1. Anticancer agents
2. Antimicrobial and antiviral compounds
3. Anti-inflammatory and analgesic agents
4. Central nervous system (CNS) active drugs
1)Anticancer Agents
Indole derivatives have demonstrated potent anticancer activity through various mechanisms, including apoptosis induction, inhibition of cell proliferation, and interference with key signaling pathways. Notable examples include:
Natural and Synthetic Indoles:
Compounds such as indole-3-carbinol (I3C) and its metabolite 3,3'-diindolylmethane (DIM) have been studied for their ability to modulate hormonal responses and induce cell cycle arrest in various cancer cell lines.
Kinase Inhibitors and Apoptotic Modulators:
Many synthetic indole derivatives act as inhibitors of kinases (e.g., protein kinase C) or induce apoptosis through mitochondrial pathways. Structural modifications that improve selectivity and potency have led to the development of several promising leads in preclinical studies.
Structure–Activity Relationships (SAR):
The efficacy of indole-derived anticancer agents often depends on the nature and position of substituents attached to the indole ring. Electron-donating and withdrawing groups can significantly influence both pharmacokinetic properties and biological activity, which informs ongoing SAR studies.
2)Antimicrobial and Antiviral Compounds
Indole derivatives have also emerged as valuable scaffolds in the fight against infectious diseases
Antibacterial Activity:
Several indole-based molecules have shown effectiveness against Gram-positive and Gram-negative bacteria. Their mechanisms often involve disruption of bacterial cell membranes or inhibition of essential enzymes, such as bacterial DNA gyrase.
Antiviral Agents:
Certain indole derivatives exhibit antiviral properties by interfering with virus replication or entry processes. For example, indole compounds have been evaluated for activity against RNA and DNA viruses, offering a promising starting point for developing new antiviral therapeutics.
Broad-Spectrum Applications:
With the rising challenge of drug-resistant pathogens, research is increasingly focused on modifying the indole nucleus to enhance antimicrobial potency and reduce resistance. Structural innovations continue to be explored to extend the spectrum of activity.
3)Anti-inflammatory and Analgesic Agents
Many indole derivatives have shown significant anti-inflammatory and analgesic effects, making them attractive candidates for managing chronic inflammatory conditions and pain:
Cyclooxygenase (COX) Inhibitors:
Some indole derivatives inhibit COX enzymes, leading to reduced production of prostaglandins involved in inflammation. This mechanism is similar to that of non-steroidal anti-inflammatory drugs (NSAIDs), but indoles can offer improved selectivity and reduced gastrointestinal side effects.
Modulation of Cytokine Production:
Beyond COX inhibition, certain indole compounds modulate the production of pro-inflammatory cytokines, thereby attenuating the inflammatory response at multiple levels.
4)Central Nervous System (CNS) Active Drugs
The indole nucleus is a critical structural component in many CNS-active drugs, leveraging its capacity to interact with neurotransmitter systems:
Serotoninergic Activity:
Indoles naturally mimic the structure of serotonin. As a result, many indole derivatives act as agonists or antagonists at serotonin receptors, influencing mood, cognition, and behavior. This is exemplified by drugs for treating depression and anxiety.
REFERENCES
Aditi Shelke*, Shritej Varhadi, Dr. Lokhande R. P., Mahadik Jay, Dhamane Yash, Indole Synthesis: A Review and Medicinal Uses of Their Derivatives, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 5, 4361-4369. https://doi.org/10.5281/zenodo.15517986
10.5281/zenodo.15517986
