Friedel-Crafts Reactivity with Sulfondiimidoyl Fluorides for the Synthesis of Heteroaryl Sulfondiimines.

Sulfur functional groups are ubiquitous in molecules used in the pharmaceutical and agrochemical industries, and within these collections sulfones hold a prominent position. The double aza-analogues of sulfones, sulfondiimines, offer significant potential in discovery chemistry but to date their applications have been limited by the lack of convenient synthetic routes. The existing methods mainly rely on imination of low-valent-sulfur intermediates, or the combination of pre-formed organometallic reagents and electrophilic S(VI)-functionalities. Herein, we describe a Friedel-Crafts-type reaction of sulfondiimidoyl fluorides with (hetero)aryls. This new SuFEx reactivity benefits from broad functional group tolerance, mild reaction conditions, and does not require the use of pre-formed organometallic reagents. The efficient use of unprotected indoles and pyrroles, as well as furan, thiophene and carbocyclic aromatics, further demonstrates the advantages of these reactions. We show that the reactivity of the sulfondiimidoyl fluorides can be tuned by switching the N-substituents, allowing an expansion of the range of coupling partners. The utility of the transformation is exemplified by the synthesis of the sulfondiimine analogue of the HIV-I reverse transcriptase-inhibitor L-737,126.

Rhodium-Catalyzed Asymmetric Cyclopropanation of Indoles with N-Triftosylhydrazones.

Here we report a general rhodium-catalyzed asymmetric intermolecular dearomative cyclopropanation of indoles using trifluoromethyl N-triftosylhydrazones as carbene precursors. The reaction enables the rapid construction of diverse cyclopropane fused indolines bearing a trifluoromethylated quaternary stereocenter in high enantioselectivities (up to 99% ee). This mild method exhibits a broad substrate scope, is compatible with various functional groups, and can even be utilized for the late-stage diversification of complex bioactive molecules. DFT calculations suggest that the formation of a key zwitterionic intermediate is responsible for the chiral induction. Overall, this approach opens up new possibilities for asymmetric cyclopropanation of challenging aromatic heterocyclic compounds.

The Influence of Different Hydrothermal Processes Used in the Preparation of Brussels Sprouts on the Availability of Glucosinolates to Humans.

Cruciferous vegetables represent a valuable source of bioactive compounds. However, there is currently a deficiency of information regarding the extent to which these compounds remain bioaccessible to the body following thermal treatment and digestion processes within the digestive tract. Accordingly, the aim of this study was to evaluate the impact of heat treatment and in vitro digestion on the level of selected bioactive compounds in Brussels sprouts. The Brussels sprouts samples were subjected to a range of thermal processing techniques, which were then followed by a simulated in vitro digestion. The investigated compounds were analyzed using UV-Vis spectrometry and liquid chromatography coupled with mass spectrometry (LC-MS). The findings revealed that the sous-vide method of cooking Brussels sprouts resulted in significantly higher losses of glucosinolates (GLS) in comparison to conventional cooking methods. No significant differences were observed with regard to isothiocyanates and indoles. The analysis of GLS following digestion revealed that the process was more effective after sous vide and traditional cooking, and slightly less effective after steam cooking. With regard to individual compounds, glucoraphanin (GRA), glucoraphenin (GIV), and gluconasturtiin (GNS) were found to be completely degraded, whereas methoxyglucobrassicin (metGBS) was the most resistant to digestion in both the sous vide and steamed Brussels sprouts. The results indicated that the process of simulating digestion had no significant impact on isothiocyanates and indoles. This suggests that, if present in the heat-treated samples, these compounds remained stable during the in vitro digestion procedure.

Photocatalytic PPh3-Mediated Synthesis of C3-Functionalized Indoles via Radical Annulation of Nitroarenes and Alkenes.

Oxidatively generated phosphine radical cations are reactive intermediates that can be used for the generation of carbon and heteroatom centered radicals via deoxygenation processes. Such P-radical cations can readily be generated via single electron transfer oxidation using a redox catalyst. Cheap and commercially available nitroarenes are ideal nitrogen sources for the construction of organic amines and N-containing heterocycles. Activation of nitroarenes with phosphines has been achieved in the ionic mode, which requires specially designed P-nucleophiles and high temperatures. Herein, we report an alternative mode of nitro activation that proceeds via a radical process. The radical strategy leads to open shell intermediates that show interesting unexplored reactivity. This is documented by the development of an economic and highly efficient synthesis of valuable indole derivatives through photocatalytic PPh3-mediated annulation of nitroarenes with alkenes showing large functional group tolerance. The method allows room-temperature activation of nitroarenes and a double C-H bond functionalization of alkenes is achieved to provide rapid access to C3-functionalized indoles, which are key structural components of diverse natural and drug molecules. Experimental mechanistic studies that are further supported by DFT calculations indicate that a nitrosoarene radical cation plays a key role in the annulation process.

Iodophor-/H2O2-Mediated 2-Sulfonylation of Indoles and N-Methylpyrrole in Aqueous Phase.

A convenient and efficient strategy for the preparation of 2-sulfonylindoles has been achieved through iodophor-/H2O2-mediated 2-sulfonylation of indoles with readily available sulfonyl hydrazides in the aqueous phase. Iodophor is commercially available and serves as the green catalyst and aqueous phase. A series of 2-sulfonylated products from indoles and N-methylpyrrole were synthesized in moderate yields in only 10 min. Control experiments were also conducted to reveal the mechanism of action. This method is environment friendly, easy to operate and suitable for a wide range of substrates.

Selective C-Methylenation of N-Unsubstituted Indoles Using CO2 Under NaBH4/I2 System.

The selective C-methylenation of N-unsubstituted indoles using CO2 as the C1 source to access diindolylmethane (DIM) and its derivatives is described. This reaction provides a novel method for four-electron reductive functionalization of CO2 with N-unsubstituted indoles via formation of C-CH2-C bonds, and a new access to molecular structures.

Host-microbe serotonin metabolism.

As a result of a long evolutionary history, serotonin plays a variety of physiological roles, including neurological, cardiovascular, gastrointestinal, and endocrine functions. While many of these activities can be accommodated within the serotoninergic activity, recent findings have revealed an unsuspected role of serotonin in orchestrating host and microbial dialogue at the tryptophan dining table, to the benefit of local and systemic homeostasis. Herein we review the dual role of serotonin at the host-microbe interface and discuss how unraveling the interconnections among the host and microbial pathways of tryptophan degradation may help to accommodate the versatility of serotonin in physiology and pathology.

Metal-Free, PPA-Mediated Fisher Indole Synthesis via Tandem Hydroamination-Cyclization Reaction between Simple Alkynes and Arylhydrazines.

A new variant of Fisher indole synthesis involving Bronsted acid-catalyzed hydrohydrazination of unactivated terminal and internal acetylenes with arylhydrazines is reported. The use of polyphosphoric acid alone either as the reaction medium or in the presence of a co-solvent appears to provide the required balance for activating the C-C triple bond towards the nucleophilic attack of the hydrazine moiety without unrepairable reactivity loss of the latter due to competing amino group protonation. Additionally, the formal hydration of acetylenes to the corresponding ketones occurs under the same conditions, making it an alternative approach for generating carbonyl groups from alkynes.

The Role of Microbiota-Related Co-Metabolites in MASLD Progression: A Narrative Review.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a growing health concern due to its increasing prevalence worldwide. Metabolic homeostasis encompasses the stable internal conditions vital for efficient metabolism. This equilibrium extends to the intestinal microbiota, whose metabolic activities profoundly influence overall metabolic balance and organ health. The metabolites derived from the gut microbiota metabolism can be defined as microbiota-related co-metabolites. They serve as mediators between the gut microbiota and the host, influencing various physiological processes. The recent redefinition of the term MASLD has highlighted the metabolic dysfunction that characterize the disease. Metabolic dysfunction encompasses a spectrum of abnormalities, including impaired glucose regulation, dyslipidemia, mitochondrial dysfunction, inflammation, and accumulation of toxic byproducts. In addition, MASLD progression has been linked to dysregulation in the gut microbiota and associated co-metabolites. Short-chain fatty acids (SCFAs), hippurate, indole derivatives, branched-chain amino acids (BCAAs), and bile acids (BAs) are among the key co-metabolites implicated in MASLD progression. In this review, we will unravel the relationship between the microbiota-related metabolites which have been associated with MASLD and that could play an important role for developing effective therapeutic interventions for MASLD and related metabolic disorders.

Abiotic/Biotic Stress and Substrate Dictated Metabolic Diversity of Azotobacter Chroococcum: Synthesis of Alginate, Antifungal n-Alkanes, Lactones, and Indoles.

The current paper deals with new metabolites of different groups produced by Azotobacter chroococcum XU1. The strain's metabolic diversity is strongly altered by different factors, and some secondary metabolites are being reported for the first time for this species. As an abiotic/biotic stress response, the strain produced a broad spectrum of indole ring-containing compounds, n-alkanes (eicosane, heneicosane, docosane, tetracosane, and hexacosane), alkanes (7-hexyl eicosane and 2-methyloctacosane), saturated fatty acids (hexanoic and octanoic acids), esters (hexadecanoic acid methyl and pentadecanoic acid-14-methyl-methyl esters), and amides (9-Octadecenamide, (Z)- and 13-Docosenamide, (Z)-). Furthermore, to mitigate the abiotic stress the strain actively produced exopolysaccharide (EPS) to biosorb the Na+ ions. Apart from these metabolites, A. chroococcum XU1 synthesized lactones, namely 1,5-d-gluconolactone and d, l-mevalonic acid lactone in response to carbon source modification. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-024-01212-x.

Electrochemical Skeletal Indole Editing via Nitrogen Atom Insertion by Sustainable Oxygen Reduction Reaction.

Skeletal molecular editing gained considerable recent momentum and emerged as a uniquely powerful tool for late-stage diversifications. Thus far, superstoichiometric amounts of costly hypervalent iodine(III) reagents were largely required for skeletal indole editing. In contrast, we herein show that electricity enables sustainable nitrogen atom insertion reactions to give bio-relevant quinazoline scaffolds without stoichiometric chemical redox-waste product. The transition metal-free electro-editing was enabled by the oxygen reduction reaction (ORR) and proved robust on scale, while tolerating a variety of valuable functional groups.

A Novel C3/C4-Fused Indole Scaffold through Acid-Catalyzed Cascade Reaction.

3,4-bridged indoles are underrepresented among the vast number of indoles described in the literature. Attempts to access 3,4-macrocyclized indoles led to the unexpected formation of a novel tetracyclic indole through intramolecular acid-catalyzed ring contraction. The herein-established one-step synthetic route provides an excellent medicinal chemistry platform for the construction of screening libraries covering a unique chemical space of indoles.

The Tryptophan Metabolite Indole-3-Propionic Acid Raises Kynurenic Acid Levels in the Rat Brain In Vivo.

Alterations in the composition of the gut microbiota may be causally associated with several brain diseases. Indole-3-propionic acid (IPrA) is a tryptophan-derived metabolite, which is produced by intestinal commensal microbes, rapidly enters the circulation, and crosses the blood-brain barrier. IPrA has neuroprotective properties, which have been attributed to its antioxidant and bioenergetic effects. Here, we evaluate an alternative and/or complementary mechanism, linking IPrA to kynurenic acid (KYNA), another neuroprotective tryptophan metabolite. Adult Sprague-Dawley rats received an oral dose of IPrA (200 mg/kg), and both IPrA and KYNA were measured in plasma and frontal cortex 90 minutes, 6 or 24 hours later. IPrA and KYNA levels increased after 90 minutes and 6 hours (brain IPrA: ~56- and ~7-fold; brain KYNA: ~4- and ~3-fold, respectively). In vivo microdialysis, performed in the medial prefrontal cortex and in the striatum, revealed increased KYNA levels (~2.5-fold) following the administration of IPrA (200 mg/kg, p.o), but IPrA failed to affect extracellular KYNA when applied locally. Finally, treatment with 100 or 350 mg IPrA, provided daily to the animals in the chow for a week, resulted in several-fold increases of IPrA and KYNA levels in both plasma and brain. These results suggest that exogenously supplied IPrA may provide a novel strategy to affect the function of KYNA in the mammalian brain.

Cinnamic Acid, Perillic Acid, and Tryptophan Metabolites Differentially Regulate Ion Transport and Serotonin Metabolism and Signaling in the Mouse Ileum In Vitro.

Phytochemicals and tryptophan (Trp) metabolites have been found to modulate gut function and health. However, whether these metabolites modulate gut ion transport and serotonin (5-HT) metabolism and signaling requires further investigation. The aim of this study was to investigate the effects of selected phytochemicals and Trp metabolites on the ion transport and 5-HT metabolism and signaling in the ileum of mice in vitro using the Ussing chamber technique. During the in vitro incubation, vanillylmandelic acid (VMA) reduced (p < 0.05) the short-circuit current, and 100 µM chlorogenic acid (CGA) (p = 0.12) and perillic acid (PA) (p = 0.14) had a tendency to reduce the short-circuit current of the ileum. Compared with the control, PA and N-acetylserotonin treatment upregulated the expression of tryptophan hydroxylase 1 (Tph1), while 100 µM cinnamic acid, indolelactic acid (ILA), and 10 µM CGA or indoleacetaldehyde (IAld) treatments downregulated (p < 0.05) the mRNA levels of Tph1. In addition, 10 µM IAld or 100 µM ILA upregulated (p < 0.05) the expression of monoamine oxidase A (Maoa). However, 10 µM CGA or 100 µM PA downregulated (p < 0.05) Maoa expression. All selected phytochemicals and Trp metabolites upregulated (p < 0.05) the expression of Htr4 and Htr7 compared to that of the control group. VMA and CGA reduced (p < 0.05) the ratios of Htr1a/Htr7 and Htr4/Htr7. These findings may help to elucidate the effects of phytochemicals and Trp metabolites on the regulation of gut ion transport and 5-HT signaling-related gut homeostasis in health and disease.

Design and Characterization of a Generalist Biosensor for Indole Derivatives.

Transcription factor (TF)-based biosensors are useful synthetic biology tools for applications in a variety of areas of biotechnology. A major challenge of biosensor circuits is the limited repertoire of identified and well-characterized TFs for applications of interest, in addition to the challenge of optimizing selected biosensors. In this work, we implement the IclR family repressor TF TtgV from Pseudomonas putida DOT-T1E as an indole-derivative biosensor in Escherichia coli. We optimize the genetic circuit utilizing different components, providing insights into biosensor design and expanding on previous studies investigating this TF. We discover novel physiologically relevant ligands of TtgV, such as skatole. The broad specificity of TtgV makes it a useful target for directed evolution and protein engineering toward desired specificity. TtgV, as an indole-derivative biosensor, is a promising genetic component for the detection of compounds with biological activities relevant to health and the gut microbiome.

Synthetic account on indoles and their analogues as potential anti-plasmodial agents.

Malaria caused by P. falciparum, has been recognized as one of the major infectious diseases causing the death of several patients as per the reports from the World Health Organization. In search of effective therapeutic agents against malaria, several research groups have started working on the design and development of novel heterocycles as anti-malarial agents. Heterocycles have been recognized as the pharmacophoric features for the different types of medicinally important activities. Among all these heterocycles, nitrogen containing aza-heterocycles should not be underestimated owing to their wide therapeutic window. Amongst the aza-heterocycles, indoles and fused indoles such as marinoquinolines, isocryptolepines and their regioisomers, manzamines, neocryptolenines, and indolones have been recognized as anti-malarial agents active against P. falciparum. The present work unleashes the synthetic attempts of anti-malarial indoles and fused indoles through cyclocondensation, Fischer-indole synthesis, etc. along with the brief discussions on structure-activity relationships, in vitro or in vivo studies for the broader interest of these medicinal chemists, working on their design and development as potential anti-malarial agents.

Microbial Indoles: Key Regulators of Organ Growth and Metabolic Function.

Gut microbes supporting body growth are known but the mechanisms are less well documented. Using the microbial tryptophan metabolite indole, known to regulate prokaryotic cell division and metabolic stress conditions, we mono-colonized germ-free (GF) mice with indole-producing wild-type Escherichia coli (E. coli) or tryptophanase-encoding tnaA knockout mutant indole-non-producing E. coli. Indole mutant E. coli mice showed multiorgan growth retardation and lower levels of glycogen, cholesterol, triglycerides, and glucose, resulting in an energy deficiency despite increased food intake. Detailed analysis revealed a malfunctioning intestine, enlarged cecum, and reduced numbers of enterochromaffin cells, correlating with a metabolic phenotype consisting of impaired gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice displayed reduction in serum levels of tricarboxylic acid (TCA) cycle intermediates and lipids. In stark contrast, a massive increase in serum melatonin was observed-frequently associated with accelerated oxidative stress and mitochondrial dysfunction. This observational report discloses functional roles of microbe-derived indoles regulating multiple organ functions and extends our previous report of indole-linked regulation of adult neurogenesis. Since indoles decline by age, these results imply a correlation with age-linked organ decline and levels of indoles. Interestingly, increased levels of indole-3-acetic acid, a known indole metabolite, have been shown to correlate with younger biological age, further supporting a link between biological age and levels of microbe-derived indole metabolites. The results presented in this resource paper will be useful for the future design of food intervention studies to reduce accelerated age-linked organ decline.

Nickel(II)-Catalyzed Formal [3+2] Cycloadditions between Indoles and Donor-Acceptor Cyclopropanes.

This article describes the development of a nickel-catalyzed regio- and diastereoselective formal [3+2] cycloaddition between N-substituted indoles and donor-acceptor cyclopropanes to synthesize cyclopenta[b]indoles. Optimized reaction conditions provide the desired nitrogen-containing cycloadducts in up to 93% yield and dr 8.6:1 with complete regioselectivity. The substrate scope showed high tolerance to various substituted indoles and cyclopropanes, resulting in the synthesis of six new cyclopenta[b]indoles and the isolation of five derivatives previously reported in the literature. In addition, a mechanistic proposal for the reaction was studied through online reaction monitoring by ESI-MS, allowing for the identification of the reactive intermediates in the Ni(II) catalyzed process. X-ray crystallography confirmed the structure and relative endo stereochemistry of the products. This method enables the fast and efficient construction of fused indolines from readily accessible starting materials.

Efficient Synthesis of Cyclohepta[b]indoles and Cyclohepta[b]indole-Indoline Conjugates via RCM, Hydrogenation, and Acid-Catalyzed Ring Expansion: A Biomimetic Approach.

Cyclohepta[b]indoles, prevalent in natural products and pharmaceuticals, are conventionally accessed via metal or Lewis acid-mediated cycloadditions with prefunctionalized substrates. Our study introduces an innovative sequential catalytic assembly for synthesizing cyclohepta[b]indoles from readily available isatin derivatives. The process involves three catalytic sequences: ring-closing metathesis, catalytic hydrogenation, and acid-catalyzed ring expansion. The RCM of 2,2-dialkene-3-oxindoles, formed by butenyl Grignard addition to 3-allyl-3-hydroxy-2-oxindoles, yields versatile spirocyclohexene-3-oxindole derivatives. These derivatives undergo further transformations, including dibromination, dihydroxylation, epoxidation, Wacker oxidation at the double bond. Hydrogenation of spirocyclohexene-3-oxindole yields spirocyclohexane-3-oxindoles. Their subsequent acid-catalyzed ring expansion/aromatization, dependent on the acid catalyst, results in either cyclohepta[b]indoles or cyclohepta[b]indole-indoline conjugates, adding a unique synthetic dimension. The utility of this methodology is exemplified through the synthesis of an A-FABP inhibitor, showcasing its potential in pharmaceutical applications.

B(C6F5)3/CPA-Catalyzed Aza-Diels-Alder Reaction of 3,3-Difluoro-2-Aryl-3H-indoles and Unactivated Dienes.

Here we report B(C6F5)3/CPA-catalyzed enantioselective aza-Diels-Alder reaction of 3,3-difluoro-2-Aryl-3H-indoles with unactivated dienes to access chiral 10,10-difluoro-tetrahydropyrido[1,2-a]indoles. This protocol allows the formation of pyrazole-based C2-quaternary indolin-3-ones with high enantioselectivities and regioselectivities. Moreover, gram-scale synthesis of the 10,10-difluoro-tetrahydropyrido[1,2-a]indole skeleton was successfully achieved without any reduction in both yield and enantioselectivity.