Indole

Last updated
Indole
Indole 2D numbered.svg
Indole-3D-balls-2.png
Indole-3D-spacefill.png
Names
Preferred IUPAC name
1H-Indole [1]
Other names
2,3-Benzopyrrole, ketole,
1-benzazole
Identifiers
3D model (JSmol)
3DMet
107693
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.004.019 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 204-420-7
3477
KEGG
PubChem CID
RTECS number
  • NL2450000
UNII
  • InChI=1S/C8H7N/c1-2-4-8-7(3-1)5-6-9-8/h1-6,9H Yes check.svgY
    Key: SIKJAQJRHWYJAI-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C8H7N/c1-2-4-8-7(3-1)5-6-9-8/h1-6,9H
    Key: SIKJAQJRHWYJAI-UHFFFAOYAI
  • C12=C(C=CN2)C=CC=C1
Properties
C8H7N
Molar mass 117.151 g·mol−1
AppearanceWhite solid
Odor Fecal or jasmine like (at extremely low concentrations)
Density 1.1747 g/cm3, solid
Melting point 52 to 54 °C (126 to 129 °F; 325 to 327 K)
Boiling point 253 to 254 °C (487 to 489 °F; 526 to 527 K)
0.19 g/100 ml (20 °C)
Soluble in hot water
Acidity (pKa)16.2
(21.0 in DMSO)
Basicity (pKb)17.6
-85.0·10−6 cm3/mol
Structure
Pna21
Planar
2.11  D in benzene
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Skin sensitising
GHS labelling:
GHS-pictogram-skull.svg GHS-pictogram-exclam.svg
Danger
H302, H311
P264, P270, P280, P301+P312, P302+P352, P312, P322, P330, P361, P363, P405, P501
Flash point 121 °C (250 °F; 394 K)
Safety data sheet (SDS)
Related compounds
Other cations
Indolium
benzene, benzofuran,
carbazole, carboline,
indene, benzothiophene,
indoline,
isatin, methylindole,
oxindole, pyrrole,
skatole, benzophosphole
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Indole is an organic compound with the formula C6H4CCNH3. Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole where one or more of the hydrogen atoms have been replaced by substituent groups. Indoles are widely distributed in nature, most notably as amino acid tryptophan and neurotransmitter serotonin. [2]

Contents

General properties and occurrence

Indole is a solid at room temperature. It occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell, [3] and is a constituent of many perfumes. It also occurs in coal tar. It has been identified in cannabis. [4] It is the main volatile compound in stinky tofu. [5]

When indole is a substituent on a larger molecule, it is called an indolyl group by systematic nomenclature.

Indole undergoes electrophilic substitution, mainly at position 3 (see diagram in right margin). Substituted indoles are structural elements of (and for some compounds, the synthetic precursors for) the tryptophan-derived tryptamine alkaloids, which includes the neurotransmitter serotonin and the hormone [6] melatonin, as well as the naturally occurring psychedelic drugs dimethyltryptamine and psilocybin. Other indolic compounds include the plant hormone auxin (indolyl-3-acetic acid, IAA), tryptophol, the anti-inflammatory drug indomethacin, and the betablocker pindolol.

The name indole is a portmanteau of the words indigo and oleum , since indole was first isolated by treatment of the indigo dye with oleum.

History

Baeyer's original structure for indole, 1869 Baeyer indole structure.png
Baeyer's original structure for indole, 1869

Indole chemistry began to develop with the study of the dye indigo. Indigo can be converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust. [7] In 1869, he proposed a formula for indole. [8]

Certain indole derivatives were important dyestuffs until the end of the 19th century. In the 1930s, interest in indole intensified when it became known that the indole substituent is present in many important alkaloids, known as indole alkaloids (e.g., tryptophan and auxins), and it remains an active area of research today. [9]

Biosynthesis and function

Indole is biosynthesized in the shikimate pathway via anthranilate. [2] It is an intermediate in the biosynthesis of tryptophan, where it stays inside the tryptophan synthase molecule between the removal of 3-phospho-glyceraldehyde and the condensation with serine. When indole is needed in the cell, it is usually produced from tryptophan by tryptophanase. [10]

Indole is produced via anthranilate and reacts further to give the amino acid tryptophan. Tryptophan biosynthesis (en).svg
Indole is produced via anthranilate and reacts further to give the amino acid tryptophan.

As an intercellular signal molecule, indole regulates various aspects of bacterial physiology, including spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence. [11] A number of indole derivatives have important cellular functions, including neurotransmitters such as serotonin. [2]

Tryptophan metabolism by human gut microbiota (
)
Microbiota-derived 3-Indolepropionic acid-notext.svg
Tryptophanase-
expressing
bacteria
IPA
I3A
IPA
I3A
AhR
Intestinal
immune
cells
PXR
Mucosal homeostasis:
↓TNF-α
↑Junction protein-
coding mRNAs
T J
Neuroprotectant:
↓Activation of glial cells and astrocytes
↓4-Hydroxy-2-nonenal levels
↓DNA damage
–Antioxidant
–Inhibits β-amyloid fibril formation
Maintains mucosal reactivity:
↑IL-22 production
Interactive icon.svg
This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut. [12] Indole is produced from tryptophan by bacteria that express tryptophanase. [12] Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA), [13] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals. [12] [14] [15] IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function. [12] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease. [12] Lactobacillaceae (Lactobacillus s.l.) species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production. [12] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR. [12] Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction. [12] AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma. [12]

Detection methods

Common classical methods applied for the detection of extracellular and environmental indoles, are Salkowski, Kovács, Ehrlich’s reagent assays and HPLC. [16] [17] [18] For intracellular indole detection and measurement genetically encoded indole-responsive biosensor is applicable. [19]

Medical applications

Indoles and their derivatives are promising against tuberculosis, malaria, diabetes, cancer, migraines, convulsions, hypertension, bacterial infections of methicillin-resistant Staphylococcus aureus (MRSA) and even viruses. [20] [21] [22] [23] [24]

Synthetic routes

Indole and its derivatives can also be synthesized by a variety of methods. [25] [26] [27]

The main industrial routes start from aniline via vapor-phase reaction with ethylene glycol in the presence of catalysts:

Indole from aniline and ethylene glycol 2.svg

In general, reactions are conducted between 200 and 500 °C. Yields can be as high as 60%. Other precursors to indole include formyltoluidine, 2-ethylaniline, and 2-(2-nitrophenyl)ethanol, all of which undergo cyclizations. [28]


Leimgruber–Batcho indole synthesis

Leimgruber-Batcho Indole Scheme.png

The Leimgruber–Batcho indole synthesis is an efficient method of synthesizing indole and substituted indoles. [29] Originally disclosed in a patent in 1976, this method is high-yielding and can generate substituted indoles. This method is especially popular in the pharmaceutical industry, where many pharmaceutical drugs are made up of specifically substituted indoles.

Fischer indole synthesis

Fischer indole reaction scheme.svg
One-pot microwave-assisted synthesis of indole from phenylhydrazine and pyruvic acid One-pot synthesis of indoles.svg
One-pot microwave-assisted synthesis of indole from phenylhydrazine and pyruvic acid

One of the oldest and most reliable methods for synthesizing substituted indoles is the Fischer indole synthesis, developed in 1883 by Emil Fischer. Although the synthesis of indole itself is problematic using the Fischer indole synthesis, it is often used to generate indoles substituted in the 2- and/or 3-positions. Indole can still be synthesized, however, using the Fischer indole synthesis by reacting phenylhydrazine with pyruvic acid followed by decarboxylation of the formed indole-2-carboxylic acid. This has also been accomplished in a one-pot synthesis using microwave irradiation. [30]

Other indole-forming reactions

Chemical reactions of indole

Basicity

Unlike most amines, indole is not basic: just like pyrrole, the aromatic character of the ring means that the lone pair of electrons on the nitrogen atom is not available for protonation. [33] Strong acids such as hydrochloric acid can, however, protonate indole. Indole is primarily protonated at the C3, rather than N1, owing to the enamine-like reactivity of the portion of the molecule located outside of the benzene ring. The protonated form has a pKa of −3.6. The sensitivity of many indolic compounds (e.g., tryptamines) under acidic conditions is caused by this protonation.

Electrophilic substitution

The most reactive position on indole for electrophilic aromatic substitution is C3, which is 1013 times more reactive than benzene. For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid tryptophan. Vilsmeier–Haack formylation of indole [34] will take place at room temperature exclusively at C3.

Indole Vilsmeyer-Haack Formylation.png

Since the pyrrolic ring is the most reactive portion of indole, electrophilic substitution of the carbocyclic (benzene) ring generally takes place only after N1, C2, and C3 are substituted. A noteworthy exception occurs when electrophilic substitution is carried out in conditions sufficiently acidic to exhaustively protonate C3. In this case, C5 is the most common site of electrophilic attack. [35]

Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde. It is the precursor to indole-3-acetic acid and synthetic tryptophan.

Gramine From Indole Scheme.png

N–H acidity and organometallic indole anion complexes

The N–H center has a pKa of 21 in DMSO, so that very strong bases such as sodium hydride or n-butyl lithium and water-free conditions are required for complete deprotonation. The resulting organometalic derivatives can react in two ways. The more ionic salts such as the sodium or potassium compounds tend to react with electrophiles at nitrogen-1, whereas the more covalent magnesium compounds (indole Grignard reagents ) and (especially) zinc complexes tend to react at carbon 3 (see figure below). In analogous fashion, polar aprotic solvents such as DMF and DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as toluene favour C3 attack. [36]

Indole anion reactions.svg

Carbon acidity and C2 lithiation

After the N–H proton, the hydrogen at C2 is the next most acidic proton on indole. Reaction of N-protected indoles with butyl lithium or lithium diisopropylamide results in lithiation exclusively at the C2 position. This strong nucleophile can then be used as such with other electrophiles.

Bergman Indole Lithiation.png

Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole, [37] as did Katritzky. [38]

Oxidation of indole

Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).

Indole NBS Oxidation.png

Cycloadditions of indole

Only the C2–C3 pi bond of indole is capable of cycloaddition reactions. Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, Padwa et al. [39] have developed this Diels-Alder reaction to form advanced strychnine intermediates. In this case, the 2-aminofuran is the diene, whereas the indole is the dienophile. Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions.

Indole Cycloaddition Padwa.png

Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented. [40] [41] [42] [43] One example is the Pictet-Spengler reaction between tryptophan derivatives and aldehydes, [44] which produces a mixture of diastereomers, leading to reduced yield of the desired product.

Hydrogenation

Indoles are susceptible to hydrogenation of the imine subunit [45] to give indolines.

ImineScope3.png

See also

Related Research Articles

In organic chemistry, arynes and benzynes are a class of highly reactive chemical species derived from an aromatic ring by removal of two substituents. Arynes are examples of didehydroarenes, although 1,3- and 1,4-didehydroarenes are also known. Arynes are examples of alkynes under high strain.

In organic chemistry, the Mannich reaction is a three-component organic reaction that involves the amino alkylation of an acidic proton next to a carbonyl functional group by formaldehyde and a primary or secondary amine or ammonia. The final product is a β-amino-carbonyl compound also known as a Mannich base. Reactions between aldimines and α-methylene carbonyls are also considered Mannich reactions because these imines form between amines and aldehydes. The reaction is named after Carl Mannich.

In retrosynthetic analysis, a synthon is a hypothetical unit within a target molecule that represents a potential starting reagent in the retroactive synthesis of that target molecule. The term was coined in 1967 by E. J. Corey. He noted in 1988 that the "word synthon has now come to be used to mean synthetic building block rather than retrosynthetic fragmentation structures". It was noted in 1998 that the phrase did not feature very prominently in Corey's 1981 book The Logic of Chemical Synthesis, as it was not included in the index. Because synthons are charged, when placed into a synthesis an uncharged form is found commercially instead of forming and using the potentially very unstable charged synthons.

The Pictet–Spengler reaction is a chemical reaction in which a β-arylethylamine undergoes condensation with an aldehyde or ketone followed by ring closure. The reaction was first discovered in 1911 by Amé Pictet and Theodor Spengler. Traditionally, an acidic catalyst in protic solvent was employed with heating; however, the reaction has been shown to work in aprotic media in superior yields and sometimes without acid catalysis. The Pictet–Spengler reaction can be considered a special case of the Mannich reaction, which follows a similar reaction pathway. The driving force for this reaction is the electrophilicity of the iminium ion generated from the condensation of the aldehyde and amine under acid conditions. This explains the need for an acid catalyst in most cases, as the imine is not electrophilic enough for ring closure but the iminium ion is capable of undergoing the reaction.

<span class="mw-page-title-main">Isatin</span> Chemical compound

Isatin, also known as tribulin, is an organic compound derived from indole with formula C8H5NO2. The compound was first obtained by Otto Linné Erdman and Auguste Laurent in 1840 as a product from the oxidation of indigo dye by nitric acid and chromic acids.

<span class="mw-page-title-main">Petasis reaction</span>

The Petasis reaction is the multi-component reaction of an amine, a carbonyl, and a vinyl- or aryl-boronic acid to form substituted amines.

<span class="mw-page-title-main">Zincke aldehyde</span>

Zincke aldehydes, or 5-aminopenta-2,4-dienals, are the product of the reaction of a pyridinium salt with two equivalents of any secondary amine, followed by basic hydrolysis. Using secondary amines the Zincke reaction takes on a different shape forming Zincke aldehydes in which the pyridine ring is ring-opened with the terminal iminium group hydrolyzed to an aldehyde. The use of the dinitrophenyl group for pyridine activation was first reported by Theodor Zincke. The use of cyanogen bromide for pyridine activation was independently reported by W. König:

Strictosidine synthase (EC 4.3.3.2) is an enzyme in alkaloid biosynthesis that catalyses the condensation of tryptamine with secologanin to form strictosidine in a formal Pictet–Spengler reaction:

<span class="mw-page-title-main">Yuehchukene</span> Chemical compound

Yuehchukene is a dimeric indole alkaloid that shows anti-fertility and estrogenic activities. Yuehchukene is isolated from the roots of plants belonging to the genus Murraya. Its natural abundance is in the range of 10-52 ppm.

<span class="mw-page-title-main">Strychnine total synthesis</span>

Strychnine total synthesis in chemistry describes the total synthesis of the complex biomolecule strychnine. The first reported method by the group of Robert Burns Woodward in 1954 is considered a classic in this research field.

<span class="mw-page-title-main">Conolidine</span> Chemical compound

Conolidine is an indole alkaloid. Preliminary reports suggest that it could provide analgesic effects with few of the detrimental side-effects associated with opioids such as morphine, though at present it has only been evaluated in mouse models.

<span class="mw-page-title-main">MN-25</span> Chemical compound

MN-25 (UR-12) is a drug invented by Bristol-Myers Squibb, that acts as a reasonably selective agonist of peripheral cannabinoid receptors. It has moderate affinity for CB2 receptors with a Ki of 11 nM, but 22x lower affinity for the psychoactive CB1 receptors with a Ki of 245 nM. The indole 2-methyl derivative has the ratio of affinities reversed however, with a Ki of 8 nM at CB1 and 29 nM at CB2, which contrasts with the usual trend of 2-methyl derivatives having increased selectivity for CB2 (cf. JWH-018 vs JWH-007, JWH-081 vs JWH-098).

<span class="mw-page-title-main">Hydrogen-bond catalysis</span> Type of organocatalysis

Hydrogen-bond catalysis is a type of organocatalysis that relies on use of hydrogen bonding interactions to accelerate and control organic reactions. In biological systems, hydrogen bonding plays a key role in many enzymatic reactions, both in orienting the substrate molecules and lowering barriers to reaction. The field is relatively undeveloped compared to research in Lewis acid catalysis.

<span class="mw-page-title-main">Akuammicine</span> Alkaloid

Akuammicine is a monoterpene indole alkaloid of the Vinca sub-group. It is found in the Apocynaceae family of plants including Picralima nitida, Vinca minor and the Aspidosperma.

<span class="mw-page-title-main">Stephacidin</span>

Stephacidin A and B are antitumor alkaloids isolated from the fungus Aspergillus ochraceus that belong to a class of naturally occurring 2,5-diketopiperazines. This unusual family of fungal metabolites are complex bridged 2,5-diketopiperazine alkaloids that possess a unique bicyclo[2.2.2]diazaoctane core ring system and are constituted mainly from tryptophan, proline, and substituted proline derivatives where the olefinic unit of the isoprene moiety has been formally oxidatively cyclized across the α-carbon atoms of a 2,5-diketopiperazine ring. The molecular architecture of stephacidin B, formally a dimer of avrainvillamide, reveals a complex dimeric prenylated N-hydroxyindole alkaloid that contains 15 rings and 9 stereogenic centers and is one of the most complex indole alkaloids isolated from fungi. Stephacidin B rapidly converts into the electrophilic monomer avrainvillamide in cell culture, and there is evidence that the monomer avrainvillamide interacts with intracellular thiol-containing proteins, most likely by covalent modification.

<span class="mw-page-title-main">Affinisine</span> Chemical compound

Affinisine is a monoterpenoid indole alkaloid which can be isolated from plants of the genus Tabernaemontana. Structurally, it can be considered a member of the sarpagine alkaloid family and may be synthesized from tryptophan via a Pictet-Spengler reaction.

<span class="mw-page-title-main">Ynone</span> Organic compounds of the form RC≡CC(=O)R’

In organic chemistry, an ynone is an organic compound containing a ketone functional group and a C≡C triple bond. Many ynones are α,β-ynones, where the carbonyl and alkyne groups are conjugated. Capillin is a naturally occurring example. Some ynones are not conjugated.

<span class="mw-page-title-main">Dregamine</span> Chemical compound

Dregamine is a naturally occurring monoterpene indole alkaloid found in several species in the genus Tabernaemontana including Ervatamia hirta and Tabernaemontana divaricata.

<span class="mw-page-title-main">Fascaplysin</span> Chemical compound

Fascaplysin is a marine alkaloid based on 12H-pyrido[1–2-a:3,4-b′]diindole ring system. It was first isolated as a red pigment from the marine sponge Fascaplysinopsis reticulata that was collected in the South Pacific near Fiji in 1988. Fascaplysin possesses a broad range of in vitro biological activities including analgesic, antimicrobial, antifungal, antiviral, antimalarial, anti-angiogenic, and antiproliferative activity against numerous cancer cell lines.

References

  1. ↑ International Union of Pure and Applied Chemistry (2014). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. p. 213. doi:10.1039/9781849733069. ISBN   978-0-85404-182-4.
  2. 1 2 3 Nelson, David L.; Cox, Michael M. (2005). Principles of Biochemistry (4th ed.). New York: W. H. Freeman. ISBN   0-7167-4339-6.
  3. ↑ Purves, Dale; Augustine, George J; Fitzpatrick, David; Katz, Lawrence C; LaMantia, Anthony-Samuel; McNamara, James O; Williams, S Mark. "Olfactory Perception in Humans". Olfactory Perception in Humans. Retrieved 20 October 2020.
  4. ↑ Oswald, Iain W. H.; Paryani, Twinkle R.; Sosa, Manuel E.; Ojeda, Marcos A.; Altenbernd, Mark R.; Grandy, Jonathan J.; Shafer, Nathan S.; Ngo, Kim; Peat, Jack R.; Melshenker, Bradley G.; Skelly, Ian; Koby, Kevin A.; Page, Michael F. Z.; Martin, Thomas J. (2023-10-12). "Minor, Nonterpenoid Volatile Compounds Drive the Aroma Differences of Exotic Cannabis". ACS Omega. 8 (42): 39203–39216. doi: 10.1021/acsomega.3c04496 . ISSN   2470-1343. PMC   10601067 . PMID   37901519.
  5. ↑ Liu, Yuping; Miao, Zhiwei; Guan, Wei; Sun, Baoguo (26 March 2012). "Analysis of Organic Volatile Flavor Compounds in Fermented Stinky Tofu Using SPME with Different Fiber Coatings". Molecules. 17 (4): 3708–3722. doi: 10.3390/molecules17043708 . PMC   6268145 . PMID   22450681.
  6. ↑ Lee, Jung Goo (21 October 2019). "The Neuroprotective Effects of Melatonin: Possible Role in the Pathophysiology of Neuropsychiatric Disease". Brain Sciences. 9 (285): 285. doi: 10.3390/brainsci9100285 . PMC   6826722 . PMID   31640239.
  7. ↑ Baeyer, A. (1866). "Ueber die Reduction aromatischer Verbindungen mittelst Zinkstaub" [On the reduction of aromatic compounds by means of zinc dust]. Annalen der Chemie und Pharmacie. 140 (3): 295–296. doi:10.1002/jlac.18661400306.
  8. ↑ Baeyer, A.; Emmerling, A. (1869). "Synthese des Indols" [Synthesis of indole]. Berichte der Deutschen Chemischen Gesellschaft. 2: 679–682. doi:10.1002/cber.186900201268.
  9. ↑ Van Order, R. B.; Lindwall, H. G. (1942). "Indole". Chem. Rev. 30: 69–96. doi:10.1021/cr60095a004.
  10. ↑ Stephanopoulos, George; Aristidou, Aristos A.; Nielsen, Jens (1998-10-17). Metabolic Engineering: Principles and Methodologies. Academic Press. p. 251. ISBN   9780080536286.
  11. ↑ Lee, Jin-Hyung; Lee, Jintae (2010). "Indole as an intercellular signal in microbial communities". FEMS Microbiology Reviews. 34 (4): 426–44. doi: 10.1111/j.1574-6976.2009.00204.x . ISSN   0168-6445. PMID   20070374.
  12. 1 2 3 4 5 6 7 8 9 Zhang LS, Davies SS (April 2016). "Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions". Genome Med. 8 (1): 46. doi: 10.1186/s13073-016-0296-x . PMC   4840492 . PMID   27102537. Lactobacillus spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125]. Clostridium sporogenes convert tryptophan to IPA [6], likely via a tryptophan deaminase. ... IPA also potently scavenges hydroxyl radicals
    Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
    Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
  13. ↑ Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G (March 2009). "Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites". Proc. Natl. Acad. Sci. U.S.A. 106 (10): 3698–3703. Bibcode:2009PNAS..106.3698W. doi: 10.1073/pnas.0812874106 . PMC   2656143 . PMID   19234110. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes.
    IPA metabolism diagram
  14. ↑ "3-Indolepropionic acid". Human Metabolome Database. University of Alberta. Retrieved 12 June 2018.
  15. ↑ Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA (July 1999). "Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid". J. Biol. Chem. 274 (31): 21937–21942. doi: 10.1074/jbc.274.31.21937 . PMID   10419516. S2CID   6630247. [Indole-3-propionic acid (IPA)] has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. ... In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity.
  16. ↑ Ehmann, Axel (1977-02-11). "The van URK-Salkowski reagent — a sensitive and specific chromogenic reagent for silica gel thin-layer chromatographic detection and identification of indole derivatives". Journal of Chromatography A. 132 (2): 267–276. doi:10.1016/S0021-9673(00)89300-0. ISSN   0021-9673. PMID   188858.
  17. ↑ Darkoh, Charles; Chappell, Cynthia; Gonzales, Christopher; Okhuysen, Pablo (December 2015). Schloss, P. D. (ed.). "A Rapid and Specific Method for the Detection of Indole in Complex Biological Samples". Applied and Environmental Microbiology. 81 (23): 8093–8097. Bibcode:2015ApEnM..81.8093D. doi:10.1128/AEM.02787-15. ISSN   0099-2240. PMC   4651089 . PMID   26386049.
  18. ↑ Gilbert, Sarah; Xu, Jenny; Acosta, Kenneth; Poulev, Alexander; Lebeis, Sarah; Lam, Eric (2018). "Bacterial Production of Indole Related Compounds Reveals Their Role in Association Between Duckweeds and Endophytes". Frontiers in Chemistry. 6: 265. Bibcode:2018FrCh....6..265G. doi: 10.3389/fchem.2018.00265 . ISSN   2296-2646. PMC   6052042 . PMID   30050896.
  19. ↑ Matulis, Paulius; Kutraite, Ingrida; Augustiniene, Ernesta; Valanciene, Egle; Jonuskiene, Ilona; Malys, Naglis (January 2022). "Development and Characterization of Indole-Responsive Whole-Cell Biosensor Based on the Inducible Gene Expression System from Pseudomonas putida KT2440". International Journal of Molecular Sciences. 23 (9): 4649. doi: 10.3390/ijms23094649 . ISSN   1422-0067. PMC   9105386 . PMID   35563040.
  20. ↑ Ramesh, Deepthi; Joji, Annu; Vijayakumar, Balaji Gowrivel; Sethumadhavan, Aiswarya; Mani, Maheswaran; Kannan, Tharanikkarasu (15 July 2020). "Indole chalcones: Design, synthesis, in vitro and in silico evaluation against Mycobacterium tuberculosis". European Journal of Medicinal Chemistry. 198: 112358. doi: 10.1016/j.ejmech.2020.112358 . ISSN   0223-5234. PMID   32361610. S2CID   218490655.
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