Indole Compounds Research Articles

Change in fat skatole and indole content in lambs switched from a concentrate-based diet indoors to alfalfa grazing for various durations before slaughter

Meat from lambs fattened on alfalfa is at risk of excessive pastoral flavours due to high levels of in-fat volatile indolic compounds (especially, skatole). Skatole has also been identified as a potential marker of interest for authenticating pasture-fed lamb meat. Here, we investigated the change in skatole and indole concentrations in kidney fat from lambs switched from an indoor-fed concentrate based diet to outdoor alfalfa grazing for various durations (0, 21, 42, 63 days) before slaughter. The study used a total of 219 lambs over 3 consecutive years. Kidney-fat skatole and indole concentrations increased from as early as 21 days on alfalfa, and then reached a plateau. Similarly, the proportion of lambs that had a kidney fat-skatole concentration above 0.15 μg/g liquid fat, a value that has been established as a sensory rejection threshold for pork, increased significantly from as early as 21 days on alfalfa and then reached a plateau. This value was reached or exceeded in a significant proportion of lambs fattened on alfalfa pastures (45.1%). However, skatole was not detected in kidney fat from 20 out of 164 alfalfa-fattened lambs (i.e., 12.2%) but was detected in 15 out of 55 concentrate-fed lambs (i.e., 27.3%). We thus conclude that while skatole content in kidney fat can inform on dietary changes made shortly before slaughter, it does not have the discrimination power needed to reliably authenticate pasture-fed lamb meat, let alone duration of finishing on pasture.

Comparison of Bioactive Secondary Metabolites and Cytotoxicity of Extracts from Inonotus obliquus Isolates from Different Host Species

Inonotus obliquus, a wood-decaying mushroom, has been used as a health-promoting supplement and nutraceutical for centuries. It is a source of bioactive compounds accumulated in both the conks (pseudosclerotia/sclerotia) and the biomass obtained in vitro. This study aimed to qualitatively and quantitatively analyze the bioelements and selected metabolites produced in mycelial cultures obtained from different host species. The mycochemical potential of mycelial cultures isolated from pseudosclerotia grown in Betula pendula, Alnus glutinosa, and Carpinus betulus was compared. Parent cultures were obtained in two types of medium (malt extract agar substrates without and with birch wood). Experimental cultures were developed in 2 L bioreactors for 10 days. The content of bioelements was determined using FAAS and FAES methods. Organic compounds were estimated using the RP–HPLC–DAD method. The cytotoxicity of the extracts was evaluated in human keratinocytes HaCaT, human skin fibroblasts BJ, human liver cancer HepG2, human melanoma A375, and mouse melanoma B16-F10. The extracts showed the presence of bioelements: sodium, potassium, magnesium, calcium, zinc, manganese, iron, and copper; phenolic acids: p-hydroxybenzoic, caffeic, p-coumaric, and protocatechuic; sterols: lanosterol, ergosterol, ergosterol peroxide; triterpene compounds: betulin, betulinic acid, inotodiol; indole compounds: L-tryptophan, tryptamine, 5-methyltryptamine, melatonin. The content of bioactive substances in the biomass was dependent on both the origin of the host species of the fungus isolate and the type of culture medium. Based on the results of this study, mycelial cultures can be proposed as a potential source of bioactive compounds and are promising naturally derived cytotoxic agents.

Indole 3-heterocyclic derivative: A potential antioxidant, antidiabetic agent and their docking study on alpha amylase

α-Amylase enzymes play a crucial role in breaking down starch molecules into simple sugar units that are easily absorbed into the bloodstream, resulting in a sudden increase in blood glucose levels. To respond this effect, there is a need for potent inhibitors that can hinder the enzymatic action of α-amylase. In this regard, indole-3-heterocycles (13−23) were synthesized via functionalizing of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile with different triazoles, tetrazole, thiazole and mercapto benzothiazole with a base. Analytical techniques like 1H, 13C NMR, HRMS and IR spectroscopy characterized the newly synthesized indole heterocycles. These indole compounds functionalized were investigated for antidiabetic properties and antioxidant potentials on varying the side-chain. The synthesized indole compounds exhibited varying inhibition compared to α-amylase standard with IC50 values ranging between 6.44±1.14 μg/mL and 29.27±1.06 μg/mL competing with standard acarbose (IC50 = 5.7 ± 0.99 μg/mL). Among the series of eleven compounds, higher activity of IC50 = 6.44 ± 1.14 μg/mL was exhibited by compound 19 against α-amylase. In addition, an antioxidant potential of IC50 values of 15.62±1.20 μg/mL and 12.00 ± 1.00 μg/mL in 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2′-casino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays, respectively. The binding interactions of indole-3-heterocycles (13–23) were evaluated via in-silico docking performed on 5KEZ enzyme's active site. The current study has shown a light on the potential antidiabetic and antioxidant properties of lead molecules.

Rhizosphere microbiome assembly mediated by consecutive monoculture triggers the replant disease of Rehmannia glutinosa

Consecutive monoculture of Rehmannia glutinosa results in severe replant disease and remarkably reduces the yield and quality. Rhizosphere microbiome plays a crucial role in soil health and plant performance. In this study, high-throughput pyrosequencing combined with a culture-dependent approach were applied to analyze the changes in rhizosphere microbiome structure and bacteria-fungi inter-kingdom associations under R. glutinosa consecutive monoculture. The results revealed a distinct separation between the newly planted (NP) and the two-year monocultured (SM). R. glutinosa consecutive monoculture resulted in a significant decline in the Shannon and Simpson diversity indices for the fungal community, and a significant decrease in relative abundances of the phyla Actinobacteria, Chloroflexi and Basidiomycota. The relative abundances of the genera Streptomyces, Arthrobacter, Bacillus, Nocardioides and Lysobacter were significantly higher in NP than in SM, while the opposite was true for Fusarium. Quantitative PCR confirmed a significant reduction in the phylum Actinobacteria and the genus Bacillus, and a significant increase in Fusarium oxysporum. Furthermore, the abundances of Actinobacteria and Bacillus strains with antagonistic activities against Fusarium oxysporum were lower in extended monoculture soils. Most of the isolated antagonistic bacteria were found to be positive for different plant growth promotion activities such as solubilization of phosphate and potassium, production of siderophore and indolic compounds. In addition, it was found that phenolic acid mixture and catalpol, identified in the root exudates of R. glutinosa, could selectively inhibit or stimulate different microbes. Moreover, the culture filtrate and volatile organic compounds produced by F. oxysporum could in turn suppress the growth of certain antagonistic bacteria. In conclusion, these findings highlight the close association between R. glutinosa replant disease and rhizosphere microbiome assembly, which was mediated by root exudates and microbe-microbe interactions.

ДИНАМИКА НЕКОТОРЫХ ПОКАЗАТЕЛЕЙ СОСТОЯНИЯ ЖИВОТНЫХ ПРИ ИССЛЕДОВАНИИ СОЕДИНЕНИЙ ИНДОЛА

A fragment of indole compounds under inhalation action on experimental animals is presented

Phosphate solubilizing bacteria inducing systemic resistance with a potential for use as biofertilizer for rice

Induced systemic resistance (ISR) and biofertilizer are two activities in plant protection from pathogens as well as an alternative to the use of traditional fertilizers. The purpose of the study was to determine other features of 4 bacteria that have the ability as phosphate solvents and produce indole and siderophore compounds that determine them as inducers of systemic resistance and indicate their possibility to be applied as biofertilizers in rice plants. This study is experimental with four (4) bacteria that have been identified and characterized molecularly: Paenibacillus alvei AP4SR, Paenibacillus alvei AP6SR, Bacillus cereus RH8SR, and Bacillus cereus RH10SR. The results showed that the characteristics of the four bacteria could be applied as biofertilizers. The ability to fix nitrogen was shown by Paenibacillus alvei AP4SR, Paenibacillus alvei AP6SR and Bacillus cereus RH10SR, while the ability to dissolve potassium was shown by Paenibacillus alvei AP4SR, Bacillus cereus RH8SR, and Bacillus cereus RH10SR. Only three isolates were able to increase plant metabolite levels, namely Paenibacillus alvei AP4SR, Bacillus cereus RH10SR and Bacillus cereus RH8SR. Bacterial inoculation had a significant effect on plant height and the number of tillers at the age of 40 days, the number of tillers/plant increased to 56.52%..

Determination of toxicity and radioprotective properties of bacterial and fungal eumelanin pigments

Purpose Determination of the protective property of melanin, an organic polymer class consisting of phenolic and/or indolic compounds isolated from bacteria and fungi, against fast neutron radiation. To show that these melanin samples, which also have antioxidant and metal chelating properties, can be used as an active ingredient for a drug to be developed against neutrons used in nuclear research and medicine. Materials and methods Bacterial and fungal media were prepared, and melanin pigments were produced and isolated. For molecular characterization of pigments, bacterial genomic DNA extraction, 16S rDNA gene amplification processes, and fungal genomic DNA extraction, ITS1, and ITS4 Gene Regions amplification were performed. The DEL assay was implemented to determine the genotoxicity properties of bacterial and fungal melanin pigments. Samples were prepared in a pad measuring 10 ml volume (60 × 15 mm) at a concentration of 0.2–1 microgram in 1% agarose gel for radiation-absorbed dose measurements. Absorption measurements were made using 241Am-Be fast neutron source and Canberra brand NP series BF3 gaseous detector to determine the neutron radiation absorption capacity of all samples. The results obtained to determine the absorption degrees of melanin samples were compared with paraffin and normal concrete, which are widely used in neutron radiation shielding studies. Results Melanin pigments were obtained using different bacteria and fungi strains. Afterwards, the fast neutron radiation absorption capacity of these purified pigments were determined. Compared to reference samples, these pigments were found to have slightly lower radiation absorbing ability. In addition to these experiments, cytotoxicity tests were carried out using the Yeast DEL assay technique to evaluate the potential for use of these organic pigments in fields such as medicine and pharmacology. According to the results obtained from the tests, it was determined that these melanin samples did not have any toxic effects. Conclusion It was determined that these melanin samples have the potential to be used as a radioprotective drug active substance to protect the tissues and cells of people exposed to neutron radiation after a nuclear accident or nuclear war. Giving a drug that will be developed by using these active ingredients before or after people are exposed to a radiation environment can provide great benefits.

New Indole-3-Propionic Acid and 5-Methoxy-Indole Carboxylic Acid Derived Hydrazone Hybrids as Multifunctional Neuroprotectors.

In light of the known neuroprotective properties of indole compounds and the promising potential of hydrazone derivatives, two series of aldehyde-heterocyclic hybrids combining those pharmacophores were synthesized as new multifunctional neuroprotectors. The obtained derivatives of indole-3-propionic acid (IPA) and 5-methoxy-indole carboxylic acid (5MICA) had good safety profiles: Hemolytic effects < 5% (200 μM) and IC50 > 150 µM were found in the majority of the SH-SY5Y and bEnd3 cell lines. The 2,3-dihydroxy, 2-hydroxy-4-methoxy, and syringaldehyde derivatives of 5MICA exhibited the strongest neuroprotection against H2O2-induced oxidative stress in SH-SY5Y cells and 6-OHDA-induced neurotoxicity in rat-brain synaptosomes. All the compounds suppressed the iron-induced lipid peroxidation. The hydroxyl derivatives were also the most active in terms of deoxyribose-degradation inhibition, whereas the 3,4-dihydroxy derivatives were able to decrease the superoxide-anion generation. Both series of compounds showed an increased inhibition of hMAO-B, with greater expression detected in the 5MICA hybrids. The in vitro BBB model with the bEnd3 cell line showed that some compounds increased the permeability of the endothelial monolayer while maintaining the tight junctions. The combined results demonstrated that the derivatives of IPA and 5MICA showed strong neuroprotective, antioxidant, MAO-B inhibitory activity and could be considered as prospective multifunctional compounds for the treatment of neurodegenerative disorders.

Synthesis, Biological Evaluation and Docking Studies of 4H‐[1,2,3] thiadiazolo[4,5‐b]indole Hybrids as Antifungal Agents

AbstractHerein, we report the synthesis of 4H‐[1,2,3]thiadiazolo[4,5‐b]indole derivatives along with their pharmacological activity against different Gram‐(+ve), Gram‐(−ve) and fungal strains. Structures of all the compounds were elucidated by NMR, HRMS, LC–MS and IR analysis methods. The biological studies revealed that 4H‐[1,2,3]thiadiazolo[4,5‐b]indole and 5‐nitro‐4H‐[1,2,3]thiadiazolo[4,5‐b]indole compounds possess good antifungal activity with IC50 values of 10.8±2.2, 16.0±0.9 and MIC values of 25 and 36, respectively. At the same time, compound 4H‐[1,2,3]thiadiazolo[4,5‐b]indole possesses weak antibacterial activity with an IC50 value of 34.1±1.0 and MIC &gt;100. Molecular docking performed on the compound 4H‐[1,2,3]thiadiazolo[4,5‐b]indole showed a high affinity with binding energy −6.0 and 5.7 kcal mol‐1 and formed key interactions with the active site of transferase enzyme (6AEF) and integrin protein (3FCU).

Biotechnological potential of Bacillus sp. S26 for alleviation of abiotic and biotic stresses in vine.

Grapevine (Vitis spp.) is one of the most cultivated fruit plants in the world. Vineyard growers apply copper-based products in these crops to prevent fungal diseases, generating worries about Cu contamination in soils and food. In this context, this study identifies prokaryotic communities associated with grapevine plants grown under different levels of Cu-contaminated soils. Moreover, the study isolates new bacteria to improve Cu resistance in plants. Soil Cu content correlated inversely with operational taxonomic units (OTUs) belonging to the groups Acidobacteria (SubGroup 2), Latescibacteria, Pedosphaeraceae, and Candidatus Udaeobacter. A total of 14 new bacterial isolates were obtained from copper-contaminated soils. These isolates produced Indolic Compounds (IC) in a range of 25 to 96µg mL- 1, highlighting bacterial strains S20 and S26 as the highest producers. These new bacteria also produced siderophores, highlighting strains S19 and S26, which removed 58 and 59% of Fe ions from the CAS complex, respectively. From the in vitro antagonistic activity against Colletotrichum spp. strains, the authors identified some bacterial strains that inhibited phytopathogen growth. Bacterial strain Bacillus sp. S26 was chosen for inoculation experiments in grapevine plants. This bacterial isolate improved the growth of grapevine plants in Cu-contaminated soils. However, growth promotion did not occur in unstressed plants. More studies are necessary for developing a new bioinoculant containing S26 cells aiming to reduce biotic and abiotic stresses in grapevine.

Synthesis, crystal structure and DFT study of tert-butyl 6-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indole-1-carboxylate

An indole compound, tert-butyl 6-chloro-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indole-1-carboxylate, was synthesized by a simple and efficient three-step substitution reaction. The structure of compounds can not be determined without the most common methods, namely, 1H NMR, 13C NMR, IR, MS. The structure of the target compound was determined by the above methods. Besides, the single crystal was obtained by solvent evaporation method, and the crystal structure data were obtained by means of X-ray diffraction and compared with the molecular crystal structure determined by density functional theory (DFT). Frontier molecular orbitals and molecular electrostatic potential energy are crucial in the study of chemical properties.

Primera evidencia de actividad enzimática nitrilasa en Xylaria sp., y su relación con la biosíntesis de ácido indol-3-acético

Endophytic fungi inhabit plant tissues internally and asymptomatically, and many of them are involved in the synthesis of bioactive metabolites of antifungal and therapeutic nature, as well as other compounds of biotechnological importance including indole derivatives, among many others. Ecologically, they provide some benefits to plants including protection against phytopathogens and promotion of root growth. In this sense, Xylaria sp. is a cellulose-decomposing fungus with biotechnological potential. It is worth mentioning that indole-3-acetic acid (IAA) also plays an extremely important role in plant–micro-organism interactions, as it is essential for physiology and proper plant morphological development. It is known that nitrile-hydrolytic enzymes (nitrilases) are involved in the synthesis of plant indole compounds; however, relatively little information is available concerning the nature of these enzymes in the fungal kingdom. In view of the above, through a biochemical and molecular-genetic approach, it has been demonstrated for the first time that Xylaria sp. carries out nitrile-hydrolytic enzyme activity using nitrogen and carbon-rich compounds as substrate. The studied strain increased its relative gene expression levels and showed mycelial growth, both in the presence of chemical compounds such as cyanobenzene and KCN. Thus, the results of this work suggest that the micro-organism is capable of degrading complex nitrogenous molecules. On the other hand, through fungal biofertilization, it was observed that Xylaria sp. promotes the development of the root system of Arabidopsis thaliana seedlings, in addition to synthesizing IAA.

Characteristics of microbiome-derived metabolomics according to the progression of alcoholic liver disease.

The prevalence and severity of alcoholic liver disease (ALD) are increasing. The incidence of alcohol-related cirrhosis has risen up to 2.5%. This study aimed to identify novel metabolite mechanisms involved in the development of ALD in patients. The use of gut microbiome-derived metabolites is increasing in targeted therapies. Identifying metabolic compounds is challenging due to the complex patterns that have long-term effects on ALD. We investigated the specific metabolite signatures in ALD patients. This study included 247 patients (heathy control, HC: n = 62, alcoholic fatty liver, AFL; n = 25, alcoholic hepatitis, AH; n = 80, and alcoholic cirrhosis, AC, n = 80) identified, and stool samples were collected. 16S rRNA sequencing and metabolomics were performed with MiSeq sequencer and liquid chromatography coupled to time-of-flight-mass spectrometry (LC-TOF-MS), respectively. The untargeted metabolites in AFL, AH, and AC samples were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Metabolic network classifiers were used to predict the pathway expression of the AFL, AH, and AC stages. The relative abundance of Proteobacteria was increased and the abundance of Bacteroides was decreased in ALD samples (p = 0.001) compared with that in HC samples. Fusobacteria levels were higher in AH samples (p = 0.0001) than in HC samples. Untargeted metabolomics was applied to quantitatively screen 103 metabolites from each stool sample. Indole-3-propionic acid levels are significantly lower in AH and AC (vs. HC, p = 0.001). Indole-3-lactic acid (ILA: p = 0.04) levels were increased in AC samples. AC group showed an increase in indole-3-lactic acid (vs. HC, p = 0.040) level. Compared with that in HC samples, the levels of short-chain fatty acids (SCFAs: acetic acid, butyric acid, propionic acid, iso-butyric acid, and iso-valeric acid) and bile acids (lithocholic acids) were significantly decreased in AC. The pathways of linoleic acid metabolism, indole compounds, histidine metabolism, fatty acid degradation, and glutamate metabolism were closely associated with ALD metabolism. This study identified that microbial metabolic dysbiosis is associated with ALD-related metabolic dysfunction. The SCFAs, bile acids, and indole compounds were depleted during ALD progression. Clinicaltrials.gov, number NCT04339725.

Structural Elucidation and Cytotoxic Activity of New Monoterpenoid Indoles from Gelsemium elegans.

Two new monoterpenoid indole alkaloids, gelselegandines F (1) and G (2), were isolated from the aerial parts of Gelsemium elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemical calculations. The ECD calculations were conducted at the B3LYP/6-311G(d,p) level and NMR calculations were carried out using the Gauge-Including Atomic Orbitals (GIAO) method. Structurally, the two new compounds possessed rare, cage-like, monoterpenoid indole skeletons. All isolated compounds and the total alkaloids extract were tested for cytotoxicity against four different tumor cell lines. The total alkaloids extract of G. elegans exhibited significant antitumor activity with IC50 values ranging from 32.63 to 82.24 ug/mL. In order to discover anticancer leads from the active extraction, both new indole compounds (1-2) were then screened for cytotoxicity. Interestingly, compound 2 showed moderate cytotoxicity against K562 leukemia cells with an IC50 value of 57.02 uM.

Bifidobacterium-derived short-chain fatty acids and indole compounds attenuate nonalcoholic fatty liver disease by modulating gut-liver axis.

Emerging evidences about gut-microbial modulation have been accumulated in the treatment of nonalcoholic fatty liver disease (NAFLD). We evaluated the effect of Bifidobacterium breve and Bifidobacterium longum on the NAFLD pathology and explore the molecular mechanisms based on multi-omics approaches. Human stool analysis [healthy subjects (n = 25) and NAFLD patients (n = 32)] was performed to select NAFLD-associated microbiota. Six-week-old male C57BL/6 J mice were fed a normal chow diet (NC), Western diet (WD), and WD with B. breve (BB) or B. longum (BL; 109 CFU/g) for 8 weeks. Liver/body weight ratio, histopathology, serum/tool analysis, 16S rRNA-sequencing, and metabolites were examined and compared. The BB and BL groups showed improved liver histology and function based on liver/body ratios (WD 7.07 ± 0.75, BB 5.27 ± 0.47, and BL 4.86 ± 0.57) and NAFLD activity scores (WD 5.00 ± 0.10, BB 1.89 ± 1.45, and BL 1.90 ± 0.99; p < 0.05). Strain treatment showed ameliorative effects on gut barrier function. Metagenomic analysis showed treatment-specific changes in taxonomic composition. The community was mainly characterized by the significantly higher composition of the Bacteroidetes phylum among the NC and probiotic-feeding groups. Similarly, the gut metabolome was modulated by probiotics treatment. In particular, short-chain fatty acids and tryptophan metabolites were reverted to normal levels by probiotics, whereas bile acids were partially normalized to those of the NC group. The analysis of gene expression related to lipid and glucose metabolism as well as the immune response indicated the coordinative regulation of β-oxidation, lipogenesis, and systemic inflammation by probiotic treatment. BB and BL attenuate NAFLD by improving microbiome-associated factors of the gut-liver axis.

Cheminformatics study of some indole compounds through QSAR modeling, ADME prediction, molecular docking, and molecular dynamic simulation to identify novel inhibitors of HCV NS5B protease

The hepatitis C virus is a viral disease that causes cirrhosis and hepatocellular carcinoma in the liver. Since the virus's discovery, significant therapeutic advances have been made. Notwithstanding, its upsurge necessitates the development of novel approaches to combating this disease. Recent studies have seen a rise in the value of plant compounds in the establishment of novel, efficient, and cost-efficient anti-HCV medications. These factors have motivated us to continuously search for novel, potent anti-HCV inhibitors, ideally with mechanisms different from those used in conventional medicine. Several filtrations processes including ADMET, molecular docking, and molecular dynamics (MD) simulation were used to choose potent hits from plant molecules deposited in the PubChem database. The binding kinetics were explored using MD simulation studies performed for 100 ns using GROMACS-2018.1. which was done to validate and supplement the findings of the virtual screening. The selected hits (with PubChem CID of 3,560,948 and 4,754,183) had preferable molecular traits that suggested they might work well as HCV inhibitors and are term as effective potential hits. The MD study confirmed the stability of the identified hit with a binding energy of −111.724 ( ± 81.668) kj/mol and mechanisms different from the FDA-approved drug (sofosbuvir) used as a reference with a binding energy of −106.132 ( ± 78.008) kj/mol. This approach could aid in the establishment and identification of novel inhibitors in pharmaceutical discovery. Experimental assessments could indeed ascertain as to if the identified molecule can be employed as an anti-HCV drug to address the ailment and confirm the reliability of our in-silico studies.

Metabolism-Guided Selective Androgen Receptor Antagonists: Design, Synthesis, and Biological Evaluation for Activity against Enzalutamide-Resistant Prostate Cancer.

A major challenge for new drug discovery in the area of androgen receptor (AR) antagonists lies in predicting the druggable properties that will enable small molecules to retain their potency and stability during further studies in vitro and in vivo. Indole (compound 8) is a first-in-class AR antagonist with very high potency (IC50 = 0.085 μM) but is metabolically unstable. During the metabolic studies described herein, we synthesized new small molecules that exhibit significantly improved stability while retaining potent antagonistic activity for an AR. This structure-activity relationship (SAR) study of more than 50 compounds classified with three classes (Class I, II, and III) and discovered two compounds (32c and 35i) that are potent AR antagonists (e.g., IC50 = 0.021 μM, T1/2 = 120 min for compound 35i). The new antagonists exhibited improved in vivo pharmacokinetics (PK) with high efficacy antiandrogen activity in Hershberger and antiandrogen Enz-Res tumor xenograft models that overexpress AR (LNCaP-AR).

Seleno-indoles trigger reactive oxygen species and mitochondrial dysfunction in Leishmania amazonensis

Leishmaniasis is an endemic disease caused by obligate intracellular protozoa of the genus Leishmania prevalent in the Americas, Africa, and Asia. Therapeutic options are limited for this disease and serious drawbacks are related to the administration of these drugs. Moreover, currently there is no vaccine against leishmaniasis, reinforcing the need to develop new therapeutic options. In the last decade several organoselenium and indolic compounds were reported for their ability to exert activity against different species of Leishmania, posing as promising scaffolds for the development of new drug candidates. In this study, we designed and synthesized a series of thirteen seleno-indoles and investigated their activity against Leishmania amazonensis promastigotes and amastigotes. The most promising seleno-indoles 2a, 2c, 2f, 2g and 3a show good activity against L. amazonensis promastigote and amastigote forms, presenting low toxicity to mammalian cells and good in silico ADMETox and druglikeness parameters, supporting the hypothesis as they being a promising scaffold for further investigation. Mechanistic studies revealed that seleno-indoles 2a, 2c, 2f, 2g and 3a can act interfering with membrane integrity, 2f, 2g and 3a also lead to mitochondrial dysfunction and ROS production, while compound 2a caused mitochondrial depolarization without alteration in ROS generation.

Stable isotope-assisted metabolite profiling reveals new insights into L-tryptophan chemotrophic metabolism of Rubrivivax benzoatilyticus

Anoxygenic photosynthetic bacteria (APB) are metabolically versatile, capable of surviving with an extended range of carbon and nitrogen sources. This group of phototrophic bacteria have remarkable metabolic plasticity in utilizing an array of organic compounds as carbon source/electron donors and nitrogen sources with sophisticated growth modes. Rubrivivax benzoatilyticus JA2 is one such photosynthetic bacterium utilizes L-tryptophan as nitrogen source under phototrophic growth mode and produces an array of indolic compounds of biotechnological significance. However, chemotrophic L-tryptophan metabolism is largely unexplored and studying L-tryptophan metabolism under chemotrophic mode would provide new insights into metabolic potential of strain JA2. In the present study, we employed stable-isotopes assisted metabolite profiling to unravel the L-tryptophan catabolism in Rubrivivax benzoatilyticus strain JA2 under chemotrophic (dark aerobic) conditions. Utilization of L-tryptophan as a nitrogen source for growth and simultaneous production of indole derivatives was observed in strain JA2. Liquid chromatography mass spectrometry (LC-MS) analysis of exo-metabolite profiling of carbon labeled L-tryptophan (13C11) fed cultures of strain JA2 revealed at least seventy labeled metabolites. Of these, only fourteen metabolites were confirmed using standards, while sixteen were putative and forty metabolites remained unidentified. L-tryptophan chemotrophic catabolism revealed multiple catabolic pathways and distinct differential catabolism of L-tryptophan under chemotropic state as compared to photo-catabolism of L-tryptophan in strain JA2.

Solar radiation-assisted one-pot synthesis of 3-alkylated indoles under catalyst-free conditions

Solar radiation-assisted green approach was developed for the chemoselective synthesis of 3-alkylated indoles via Yonemitsu-type condensation under catalyst-free conditions. The desired products were formed by one-pot three-component reaction of indole, aromatic aldehydes, and β-dicarbonyl compounds in polyethylene glycol-400 (PEG-400). The scope and generality of the presented approach were extended by various aromatic aldehydes and CH activated compounds. Using non-volatile solvent and renewable energy resources, absence of any catalyst, energy conservation, and the selective production of heterodimer product instead of homodimer adducts such as bisindole or xanthine, increase the economic and environmental effectiveness of the present protocol.