Indole Molecules Research Articles

Comment on “On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility” Phys. Chem. Chem. Phys., 2016, 18, 23006

In a recent article, Phys. Chem. Chem. Phys., 2016, 18, 23006, MD simulations have been used to clarify why indole is much more soluble in methanol than in water. Structural data indicate that water and methanol make very similar interactions with the indole molecule and do not provide clues to rationalize the origin of the solubility difference. In the present comment, I have shown that the relevant quantity is the magnitude of the reversible work of cavity creation. The latter magnitude proves to be markedly larger in water than in methanol, clarifying why most non-ionic solutes, with the exception of molecules able to form multiple H-bonds, such as urea, are more soluble in methanol.

Room-temperature surface-assisted reactivity of a melanin precursor: silver metal–organic coordination versus covalent dimerization on gold

The ability of catecholamines to undergo oxidative self-polymerization provides an attractive route for preparation of coatings for biotechnology and biomedicine applications. However, efforts toward developing a complete understanding of the mechanism that underpins polymerization have been hindered by the multiple catechol crosslinking reaction pathways that occur during the reaction. Scanning tunneling microscopy allows the investigation of small molecules in a reduced-complexity environment, providing important insight into how the intermolecular forces drive the formation of supramolecular assemblies in a controlled setting. Capitalizing on this approach, we studied the self-assembly of 5,6-dihydroxy-indole (DHI) on Au(111) and Ag(111) to investigate the interactions that affect the two-dimensional growth mechanism and to elucidate the behavior of the catechol group on these two surfaces. X-ray photoelectron spectroscopy, together with density functional theory and Monte Carlo modeling, helps unravel the differences between the two systems. The molecules form large ordered domains, yet with completely different architectures. Our data reveal that some of the DHI molecules deposited on Ag are in a modified redox state, with their catechol group oxidized into quinone. On Ag(111), the molecules are deposited in long-range lamellar patterns stabilized by metal-organic coordination, while covalent dimer pairs are observed on Au(111). We also show that the oxidation susceptibility is affected by the substrate, with the DHI/Au remaining inert even after being exposed to O2 gas.

Reply to the 'Comment on "On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility" Phys. Chem. Chem. Phys., 2018, 20, DOI: '.

In his comment on a recent publication by us, G. Graziano claims that solubility differences of indole in methanol and water can be rationalized by the reversible work needed to create a cavity in the solvent of the size of the solute, in this case indole. This quantity, he argues, is closely related to the solvent accessible surface area, which is greater for methanol compared with water, thus making indole more soluble in the former solvent. G. Graziano asserts that it is this property which is responsible for the large difference between the solubilities of indole in methanol and water. Further, G. Graziano claims that the differences in excess entropies and in distance distribution functions of indole in methanol and water and in methanol and water as a cosolvent found in our original work (Henao, et al., Phys. Chem. Chem. Phys., 2016, 18, 23006) are too "small" to be able to account for the differences in solubility of the indole molecule. We show in this work that the differences found by us are not small, by displaying some selected distance distribution functions in an alternative way to that described in our original paper. In fact we conclude that the differences in these functions are quantitatively greater than those found by Graziano in his comment. Secondly, we show in this reply that although the increase of the solvent accessible surface area may rationalize the differences in the indole-methanol and indole-water binary systems, and thus the work required for cavity creation, it is insufficient to fully account for the increase of indole solubility in water by the addition of very small quantities of methanol in the ternary system indole-methanol-water. In other words, as stated in our original paper, methanol is actively changing the solvation shell and not just passively increasing the solvent accessible surface area around indole. As a result of these additional analyses, we conclude that our work on the solvation differences of indole in water and methanol successfully captures differences in the solvation shells of both solvents around indole in both binary and ternary systems. Finally, while we do agree that Graziano's calculations are able to capture the role of cavity creation to explain differences in solubility, we think that our results concerning the quantification of changes in molecular interaction should be added to the calculations suggested by him to lead to a full description of the solubility.

An Integrated Multi-QSAR Modeling Approach for Designing Knoevenagel- Type Indoles with Enhancing Cytotoxic Profiles.

Unconventional Knoevenagel-type indoles have been the topic of interest of many synthetic chemists because of its promising efficacy in different diseases including cancer. To explore the structural requirements of Knoevenagel-type cytotoxic indoles for higher efficacy. Multi-QSAR modeling (MLR, ANN, SVM, Bayesian classification, HQSAR and Topomer CoMFA) was performed on these analogs. All these modeling techniques were validated individually and interpreted with the experimental SAR observations. Phenyl or p-methoxyphenyl substitution at 2nd position, electron withdrawing groups (such as sulphonyl, cyano etc.) at 3rd position and methoxy substation at 5th position of the indole scaffold may favor cytotoxicity. Eight new indole molecules were predicted from the developed QSAR models. These newly designed compounds may bind to the colchicine binding site of the tubulin protein as suggested by the molecular docking study.

Fluorescence anisotropy of indole molecules under two-photon excitation in the spectral range of 485–510 nm

Decay of polarized fluorescence in indole dissolved in propylene glycol under two-photon excitation by femtosecond laser pulses in the wavelength range of 485–510 nm has been studied. It is shown that under the experimental conditions used the fluorescence decay signal can be well described by a single excited state lifetime τf and a single rotation diffusion time τrot. By processing the data obtained, the times τf and τrot as well as anisotropy parameter r 0 characterizing the symmetry of two-photon excitation of indole molecules have been determined. Decreasing of the anisotropy parameter r0 down to zero under two-photon excitation energy higher than 5.1 eV has been observed. Interpretation of the obtained results have been done on the basis of ab initio quantum-mechanical computations. A model of energy relaxation under the condition of twophoton excitation of indole in a polar solvent has been discussed.

Antiviral activity of arbidol hydrochloride against herpes simplex virus I in vitro and in vivo

Herpes simplex virus type 1 (HSV-1) causes significant human diseases ranging from skin lesions to encephalitis, especially in neonates and immunocompromised hosts. The discovery of novel anti-HSV-1 drugs with low toxicity is required for public health. Arbidol hydrochloride (ARB) is an indole derivative molecule with broad-spectrum antiviral activity. In this study, the antiviral effects of ARB against HSV-1 infection were evaluated in vitro and in vivo. The results showed that ARB presents significant inhibitory effect on HSV-1 plaque formation and generation of progeny virus, with EC50 values (50% effective concentration) of 5.39 µg/mL (10.49 µM) and 2.26 µg/mL (4.40 µM), respectively. Moreover, time-of-addition and time-of-removal assays further suggested that ARB has viral inhibitory effects when added up to 12 h post-infection (p.i.), which could be further corroborated by determining the expression of viral immediate-early (ICP4, ICP22 and ICP27), early (ICP8 and UL42) and late (gB, gD, gH, VP1/2 and VP16) genes by real-time quantitative PCR as well as the expression of viral protein ICP4 and ICP8 at 6 h and 12 h p.i. Results of the in vivo study showed that ARB could reduce guinea pig skin lesions caused by HSV-1 infection. Conclusively, this report offers new perspectives in the search for therapeutic measures in the treatment of HSV-1 infection.

Study of the relaxation rate of photoexcited indole molecules by the interferometric pump-and-probe method at picosecond resolution

We present a new interferometric method that can be used for studying the dynamics of photoinduced processes in biologically important molecules at ultrahigh temporal resolution. The method is based upon the detection of changes in the refractive index of a substance excited by pulsed radiation of a femtosecond laser, which are measured by the pump-and-probe technique using time-delayed pulses of the same laser. The high sensitivity and stability of the interferometer allow this method to be used for monitoring variation of the concentration of short-lived excited states of biomolecules in solution. The proposed method has been verified by application to indole solutions in propylene glycol. The upper estimate of the lifetime of photoexcited indole molecules in solution amounted to about 40 ps.

Synthesis and Biological Evaluation of Hybrid 1,5- and 2,5-Disubstituted Indoles as Potentially New Antitubercular Agents.

Tuberculosis (TB) is the second leading cause of mortality worldwide being a highly contagious and insidious illness caused by Mycobacterium tuberculosis, Mtb. Additionally, the emergence of multidrug-resistant and extensively drug-resistant strains of Mtb, together with significant levels of co-infection with HIV and TB (HIV/TB) make the search for new antitubercular drugs urgent and challenging. This work was based on the hypothesis that an active compound could be obtained if substituents present in some other active compounds were attached on a core of an important structure, in this case the indole scaffold, thus generating a hybrid compound. A QSAR-oriented design based on classification and regression models along with the estimation of physicochemical and biological properties have also been used to assist in the selection of compounds. Chosen compounds were synthesized using various synthetic procedures and evaluated against M. tuberculosis H37Rv strain. Selected compounds possess substituents at positions C5, C2 and N1 of the indole ring. The substituents involve p-halophenyl, pyridyl, benzyloxy and benzylamine groups. Four compounds were synthesised using suitable synthetic procedures to attain the desired substitution at the indole core. From these, three compounds are new and have been fully characterized, and tested in vitro against the H37Rv ATCC27294T Mtb strain, using isoniazid as a control. One of them, compound 2, with the pyridyl group at N1, has an experimental log (1/MIC) very close to 5 and can be considered as being (weakly) active. In fact, it is more active than 64% of all indole molecules in our data sets of experimental results from literature. The most active indole in this data sets has log (1/MIC)=5.93 with only 6 compounds with log (1/MIC) above 5.5. Despite the lower activity found for the tested compounds, when compared to other reported indole-derivatives, these structures, which rely on a hybrid design concept, may constitute interesting scaffolds to prepare a new family of TB inhibitors with improved activity.

Low-Energy Electron Interaction with Melatonin and Related Compounds.

The electron attaching properties and fragmentation of temporary negative ions of melatonin and its biosynthetic precursor tryptophan are studied in vacuo using dissociative electron attachment (DEA) spectroscopy. The experimental findings are interpreted in silico with the support of Hartree-Fock and density functional theory calculations of empty orbital energies and symmetries, and evaluation of the electron affinities of the indolic molecules under investigation. The only fragment anions formed by DEA to melatonin at incident electron energies below 2 eV are associated with the elimination of a hydrogen atom (energetically favored from the NH site of the pyrrole ring, leaving the ring intact) or a CH3· radical from the temporary molecular negative ion. Opening of the pyrrole ring of melatonin is not detected over the whole electron energy range of 0-14 eV. The DEA spectra of l- and d-tryptophan are almost identical under the present experimental conditions. The adiabatic electron affinity of melatonin is predicted to be -0.49 eV at the B3LYP/6-31+G(d) level, indicating that the DEA mechanism in melatonin is likely to be present in most life forms given the availability of low energy electrons in living systems in both plant and animal kingdoms. In particular, H atom donation usually associated with free-radical scavenging activity can be stimulated by electron attachment and N-H bond cleavage at electron energies around 1 eV.

Potential drug – nanosensor conjugates: Raman, infrared absorption, surface – enhanced Raman, and density functional theory investigations of indolic molecules

An extremely important aspect of planning cancer treatment is not only the drug efficiency but also a number of challenges associated with the side effects and control of this process. That is why it is worth paying attention to the promising potential of the gold nanoparticles combined with a compound treated as a potential drug.This work presents Raman (RS), infrared absorption (IR) and surface–enhanced Raman scattering (SERS) spectroscopic investigations of N–acetyl–5–methoxytryptamine (melatonin) and α–methyl–dl–tryptophan, regarding as anti breast cancer agents. The experimental spectroscopic analysis was supported by the quantum-chemical calculations based on the B3LYP hybrid density functional theory (DFT) at the B3LYP 6–311G(d,p) level of theory.The studied compounds were adsorbed onto two colloidal gold nanosensors synthesized by a chemical reduction method using sodium borohydride (SB) and trisodium citrate (TC), respectively. Its morphology characteristics were obtained using transmission electron microscopy (TEM). It has been suggested that the NH moiety from the aromatic ring, a well-known proton donor, causes the formation of hydrogen bonds with the negatively charged gold surface.

Biosynthesis of indigo in Escherichia coli expressing self-sufficient CYP102A from Streptomyces cattleya

Cytochrome P450 monooxygenases (CYP) are a superfamily of heme-thiolate proteins which catalyze the incorporation of oxygen atoms into substrates. Here, a self-sufficient CYP102A from Streptomyces cattleya (CYP102A_scat) was cloned, produced recombinantly in Escherichia coli strain BL21 (DE3), and the characteristic features were investigated. However, unlike other self-sufficient CYP102A enzymes that have been reported, CYP102A_scat was found to be able to catalyze intracellular hydroxylation of indole molecules with 3-C specific regioselectivity. Consequently, E. coli strains producing CYP102A_scat could synthesize approximately 1.0 g/L of indigo in LB media. Optimization of indigo synthesis was investigated through additional feeding of indole precursors such as glucose, l-tryptophan, and indole. Indigo production reached up to 3.8 ± 0.1 g/L by adding 20 μM of extracellular indole and 0.2 mM of l-tryptophan to the LB media. To our knowledge, this is a record and the highest yield achieved so far.

Development of Novel Indole Molecules for the Screening of Anti-Inflammatory Activity.

In the present work, some new 5-[2(3)-dialkylamino alkoxy] Indole 2,3-diones were prepared from 5-hydroxy isatin. A mixture of 5-hydroxy isatin, dialkylamino alkylhalide in alcoholic potassium hydroxide was stirred at room temperature for 6h to get the 5-[2(3)-dialkylamino alkoxy] Indole 2,3-diones. The structures of the products were characterized by IR, NMR, MASS Spectral studies. All the compounds were evaluated for anti-inflammatory activity. Some of these compounds showed good anti-inflammatory activity compared with standard compound Indomethacin.

Copper-Catalyzed anti-Markovnikov Hydroindolation of Terminal Alkynes: Regioselective Synthesis of Bis(indolyl)alkanes.

An efficient copper-catalyzed intermolecular hydroindolation reaction of terminal aryl alkynes to expeditiously synthesize bis(indolyl)alkanes in moderate to high yields is described. The double nucleophilic addition of two molecules of indole to one molecule of alkyne occurs in a tandem manner through an anti-Markovnikov pathway. Various arenes and alkynes allow for this transformation. Preliminary mechanistic study sheds light on the observed regioselectivity involving a Cu-vinylidene complex, and 3-styryl-1H-indole as probable intermediates.

ChemInform Abstract: Non‐Redox Metal Ion Promoted Oxidative Coupling of Indoles with Olefins by the Palladium(II) Acetate Catalyst Through Dioxygen Activation: Experimental Results with DFT Calculations.

Developing new catalytic technologies through C–H bond activation to synthesize versatile pharmaceuticals has attracted much attention in recent decades. This work introduces a new strategy in catalyst design for Pd(II)-catalyzed C–H bond activation in which non-redox metal ions serving as Lewis acids play significant roles. In the oxidative coupling of indoles with olefins using dioxygen, it was found that Pd(OAc)2 alone as the catalyst is very sluggish at ambient temperature which provided a low yield of the olefination product, whereas adding non-redox metal ions to Pd(OAc)2 substantially improves its catalytic efficiency. In particular, it provided bis(indolyl)methane derivatives as the dominant product, a category of pharmacological molecules which could not be synthesized by Pd(II)-catalyzed oxidative coupling previously. Detailed investigations revealed that the reaction proceeds by heterobimetallic Pd(II)/Sc(III)-catalyzed oxidative coupling of an indole with an olefin followed by Sc(III)-catalyzed addition with a second indole molecule. DFT calculations disclosed that the formation of heterobimetallic Pd(II)/Sc(III) species substantially decreases the C–H bond activation energy barrier, and shifts the rate determining step from C–H bond activation of indole to the olefination step. This non-redox metal ion promoted Pd(II)-catalyzed C–H bond activation may offer a new opportunity for catalyst design in organic synthesis, which has not been fully recognized yet.

Indole Molecules as Inhibitors of Tubulin Polymerization: Potential New Anticancer Agents, an Update (2013–2015)

Discovery of new indole-based tubulin polymerization inhibitors will continue to dominate the synthetic efforts of many medicinal chemists working in the field. The indole ring system is an essential part of several tubulin inhibitors identified in the recent years. The present review article will update the synthesis, anticancer and tubulin inhibition activities of several important new indole classes such as 2-phenylindoles (28, 29 & 30), oxindoles (35 & 38), indole-3-acrylamides (44), indolines (46), aroylindoles (49), carbozoles (75, 76 & 82), azacarbolines (87) and annulated indoles (100-105).

Expression Profiling of Glucosinolate Biosynthetic Genes in Brassica oleracea L. var. capitata Inbred Lines Reveals Their Association with Glucosinolate Content.

Glucosinolates are the biochemical compounds that provide defense to plants against pathogens and herbivores. In this study, the relative expression level of 48 glucosinolate biosynthesis genes was explored in four morphologically-different cabbage inbred lines by qPCR analysis. The content of aliphatic and indolic glucosinolate molecules present in those cabbage lines was also estimated by HPLC analysis. The possible association between glucosinolate accumulation and related gene expression level was explored by principal component analysis (PCA). The genotype-dependent variation in the relative expression level of different aliphatic and indolic glucosinolate biosynthesis genes is the novel result of this study. A total of eight different types of glucosinolates, including five aliphatic and three indolic glucosinolates, was detected in four cabbage lines. Three inbred lines BN3383, BN4059 and BN4072 had no glucoraphanin, sinigrin and gluconapin detected, but the inbred line BN3273 had these three aliphatic glucosinolate compounds. PCA revealed that a higher expression level of ST5b genes and lower expression of GSL-OH was associated with the accumulation of these three aliphatic glucosinolate compounds. PCA further revealed that comparatively higher accumulation of neoglucobrassicin in the inbred line, BN4072, was associated with a high level of expression of MYB34 (Bol017062) and CYP81F1 genes. The Dof1 and IQD1 genes probably trans-activated the genes related to biosynthesis of glucoerucin and methoxyglucobrassicin for their comparatively higher accumulation in the BN4059 and BN4072 lines compared to the other two lines, BN3273 and BN3383. A comparatively higher progoitrin level in BN3273 was probably associated with the higher expression level of the GSL-OH gene. The cabbage inbred line BN3383 accounted for the significantly higher relative expression level for the 12 genes out of 48, but this line had comparatively lower total glucosinolates detected compared to the other three cabbage lines. The reason for the genotypic variation in gene expression and glucosinolate accumulation is a subject of further investigation.

Antioxidant and renoprotective activity of 2-hydroxypropyl-β-cyclodextrin in nephrectomized rats.

Oxidative stress is known to be involved in the pathogenesis of chronic renal failure (CRF). In this study, the effect of cyclodextrins (CDs) on oxidative stress and CRF was investigated using 5/6 nephrectomized rats as model animals. CRF model rats were divided into five groups and treated for 8 weeks as follows: control, α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-CD (HP-β-CD). Blood was collected from the rats after 4 and 8 weeks for an analysis of renal function and oxidative stress tests were carried out. An oral administration of HP-β-CD over an 8-week period resulted in a significant decrease in serum indoxyl sulphate, creatinine and urea nitrogen levels, compared with the other CDs. The ingestion of HP-β-CD also resulted in an increase in antioxidant potential, compared with the other CDs. In in vitro studies, the interaction of HP-β-CD with a uremic toxin, indole molecule, was much higher than that for the other CDs, as evidenced by Proton nuclear magnetic resonance ((1) H NMR) measurements. These results suggest that the ingestion of HP-β-CD might result in a significant reduction in the levels of pro-oxidants in the gastrointestinal tract, such as uremic toxins, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation.

Non-redox metal ion promoted oxidative coupling of indoles with olefins by the palladium(ii) acetate catalyst through dioxygen activation: experimental results with DFT calculations.

Developing new catalytic technologies through C-H bond activation to synthesize versatile pharmaceuticals has attracted much attention in recent decades. This work introduces a new strategy in catalyst design for Pd(ii)-catalyzed C-H bond activation in which non-redox metal ions serving as Lewis acids play significant roles. In the oxidative coupling of indoles with olefins using dioxygen, it was found that Pd(OAc)2 alone as the catalyst is very sluggish at ambient temperature which provided a low yield of the olefination product, whereas adding non-redox metal ions to Pd(OAc)2 substantially improves its catalytic efficiency. In particular, it provided bis(indolyl)methane derivatives as the dominant product, a category of pharmacological molecules which could not be synthesized by Pd(ii)-catalyzed oxidative coupling previously. Detailed investigations revealed that the reaction proceeds by heterobimetallic Pd(ii)/Sc(iii)-catalyzed oxidative coupling of an indole with an olefin followed by Sc(iii)-catalyzed addition with a second indole molecule. DFT calculations disclosed that the formation of heterobimetallic Pd(ii)/Sc(iii) species substantially decreases the C-H bond activation energy barrier, and shifts the rate determining step from C-H bond activation of indole to the olefination step. This non-redox metal ion promoted Pd(ii)-catalyzed C-H bond activation may offer a new opportunity for catalyst design in organic synthesis, which has not been fully recognized yet.

High-Resolution Far-Infrared Spectroscopy of N-Substituted Two-Ring Polycyclic Aromatic Hydrocarbons: An Extended Study.

Polycyclic aromatic hydrocarbons (PAHs) and their N-substituted derivatives are among the largest species for which gas-phase high-resolution spectroscopy can be performed nowadays. In this paper we report the observation and analysis of spectra from several N-substituted two-ring PAHs, all taken in the "fingerprint" far-infrared region (<850 cm(-1)). Together with accurate measurements of their pure rotational transitions in the millimeter and submillimeter ranges, these synchrotron-based Fourier transform infrared (FTIR) measurements provide an accurate description of the rotational energy levels in the ground and low-energy excited vibrational states of these species. To complement the experimental data, anharmonic DFT calculations were performed to obtain relatively accurate rotational and vibrational parameters. The calculated results strongly support the rotational analysis and provide a good estimate of the equilibrium structures for each species. Extended measurements, analysis, and calculations are presented here for the far-IR bands of quinoline (C9H7N), isoquinoline (C9H7N), quinoxaline (C8H6N2), quinazoline (C8H6N2), [1,5]-naphthyridine (C8H6N2), [1,6]-naphthyridine (C8H6N2), and indole (C8H7N) molecules.

Seeding for sirtuins: microseed matrix seeding to obtain crystals of human Sirt3 and Sirt2 suitable for soaking.

Sirtuins constitute a family of NAD(+)-dependent enzymes that catalyse the cleavage of various acyl groups from the ℇ-amino group of lysines. They regulate a series of cellular processes and their misregulation has been implicated in various diseases, making sirtuins attractive drug targets. To date, only a few sirtuin modulators have been reported that are suitable for cellular research and their development has been hampered by a lack of structural information. In this work, microseed matrix seeding (MMS) was used to obtain crystals of human Sirt3 in its apo form and of human Sirt2 in complex with ADP ribose (ADPR). Crystal formation using MMS was predictable, less error-prone and yielded a higher number of crystals per drop than using conventional crystallization screening methods. The crystals were used to solve the crystal structures of apo Sirt3 and of Sirt2 in complex with ADPR at an improved resolution, as well as the crystal structures of Sirt2 in complex with ADPR and the indoles EX527 and CHIC35. These Sirt2-ADPR-indole complexes unexpectedly contain two indole molecules and provide novel insights into selective Sirt2 inhibition. The MMS approach for Sirt2 and Sirt3 may be used as the basis for structure-based optimization of Sirt2/3 inhibitors in the future.