Indole Fragment Research Articles

Theoretical–Cheminformatic Study of Four Indolylphytoquinones, Prospective Anticancer Candidates

Background/Objectives: Breast cancer is a disease with a high mortality rate worldwide; consequently, urgent achievements are required to design new greener drugs, leaving natural products and their derivatives as good options. A constant antineoplastic effect has been observed when the phytoproduct contains an indole fragment. Methods: Therefore, the objective of this work was to carry out a thoughtful computational study to perform an appropriate evaluation of four novel molecules of the class of the 3-indolylquinones as phytodrug candidates for antineoplastic activity: thymoquinone (TQ), 2,6-dimethoxy-1,4-benzoquinone (DMQ), 2,3-dimethoxy-5-methyl-1,4-benzoquinone (DMMQ), and 2,5-dihydroxy-1,4-benzoquinone (DHQ). It is important to highlight that the obtained computational results of the target compounds were compared-correlated with the theoretical and experimental literature data previously reported of several indolylquinones: indolylperezone, indolylisoperezone, indolylmenadione, and indolylplumbagin (IE-IH, respectively). Results: The results revealed that the studied structures possibly presented antineoplastic activity, in addition to the fact that the reactivity parameters showed that two of the evaluated compounds have the option to present IC50 values lower than or similar to 25 mg/mL, activity like that of indolylisoperezone; moreover, they show molecular coupling to PARP-1. Finally, the prediction of the calculated physicochemical parameters coincides with the Lipinski and Veber rules, indicating that the adsorption, metabolism, and toxicity parameters are acceptable for the studied compounds, obtaining high drug score values. Conclusions: Finally, a comparison between the proposed molecules and others previously synthesized was appropriately performed, establishing that the synthesis of the studied compounds and the determination of their pharmacological properties in an experimental manner are of interest.

Synthesis of drimanyl indole fragments of drimentine alkaloids and their antibacterial activities

Two types of drimanyl indole fragments of drimentine alkaloids were synthesized and evaluated their in vitro antibacterial activities using minimum inhibitory concentration. Analysis of structure–activity relationship against Ralstonia solanacearum revealed that fragment I exhibited superior inhibitory activity compared to fragment II. Notably, free NH of the indole motif was essential for antibacterial activity, while C12OH of the drimane skeleton was beneficial for enhancing the inhibitory effect. Compound 2, possessing these structural features, showed the highest activity to R. solanacearum among all the tested compounds with a MIC value of 8 µg/mL, indicating its potential as a promising lead for the development of novel antibiotics.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides.

Despite recent advancements in catalytic synthesis of axial chirality, reports on non-biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho-aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides

Despite recent advancements in catalytic synthesis of axial chirality, reports on non‐biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho‐aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Synthesis of 5,5′-Dinitro- and 5,5′-Diaminobis(cyclopenta[<i>b</i>]indoles) Bound at <i>N</i><sup>4</sup>,<i>N</i><sup>4′</sup> Atoms with a Dioxoalkane Spacer

Upon condensation of 2 equiv. of 3R*,3aR*,8bS*-3-iodo-7-methyl-1,2,3,3а,4,8b-hexahydrocyclopenta[b]indole with 1 equiv. of glutaric or decanedicarboxylic acid dichloranhydride [N4,N4′-di-(3R*,3aR*,8bS*,3′R*,3a′R*,8b′S*)- and N4,N4′-di-(3aR*,3aR*,8bS*,3′S*,3a′S*,8b′R*)-3-iodo-7-methyl-1,2,3,3а,4,8b-hexahydrocyclopenta[b]indolyl]alkanediamides were synthesized. Their didehydrohalogenation to 3aR*,8bR*,3a′R*,8b′R*- and 3aS*,8bS*,3a′R*,8b′R*-1,3a,4,8b-tetrahydroanalogues was carried out by boiling these diiodides in piperidine. The presence of rotamerism in the products of dehydrohalogenation was shown, which is manifested by doubling the signals in the NMR spectra in different ratios. Nitration with trifluoroacetyl nitrate in CH2Cl2 yielded their 5,5′-dinitro analogs, which, when reacted with freshly prepared Fe(OH)2, along with 5,5′-diamino derivatives, also formed 5-amino-5′-nitro-substituted products of incomplete reduction. When a nitro group or an amino group appears at the C5 and C5′ carbon atoms of the cyclopenta[b]indole fragments, the doubling of the signals in the NMR spectra disappears. The interaction of a 5,5′-diamino derivative (n = 8) with decanedicarboxylic acid dichloride yielded a compound with 30 atoms in the macrocyclic ring.

Synthesis and in silico ADMET prediction of the properties of novel sulfonyl indole derivatives

The article presents a method for synthesizing sulfonyl-derived indoles by rearranging the corresponding N-arylhydrazones through boiling in acetic acid saturated with dry hydrogen chloride and the addition of anhydrous zinc chloride. The ADMET resource was used to predict the pharmacokinetic indicators of absorption, distribution, metabolism, and excretion of the synthesized compounds. The study compared the predicted activity of synthesized compounds to that of active drugs containing an indole fragment, specifically indole-3-carbinol and diindolylmethane. The results indicate that the introduction of a sulfonyl group has a positive effect on the pharmacokinetic indicators of the synthesized compounds, which are comparable to those of the active drugs. Sulphonyl-derived indoles have the potential for oral administration due to their good indicators of intestinal absorption (0.009–0.097). Additionally, there is no negative effect on the central nervous system as indicated by their indicators of penetration through the blood-brain barrier (0.003–0.008). Furthermore, the compounds did not exhibit inhibition of cytochrome P450 (CYP) enzymes. Rats are potential candidates for further in vivo studies due to their low rates of mutagenicity, carcinogenicity, and acute toxicity.

Two 5-Methoxyindole Carboxylic Acid-Derived Hydrazones of Neuropharmacological Interest: Synthesis, Crystal Structure, and Chemiluminescent Study of Radical Scavenging Properties

Given the importance of molecular structure in pharmacological activity and interaction with biological receptors, we conducted a study on the 3,4-dihydroxybenzaldehyde hydrazone derivative of 5-methoxy-indole carboxylic acid (5MICA) and a newly synthesised analogue bearing a 2-methoxy-4-hydroxyphenyl ring using single-crystal X-ray diffraction. We studied the ability of the two compounds to scavenge hypochlorite ions using luminol-enhanced chemiluminescence and their potential to modulate oxidative damage induced by iron on the biologically significant molecules lecithin and deoxyribose in order to evaluate possible antioxidant and prooxidant effects. The X-ray study revealed highly conserved geometry and limited rotation and deformation freedom of the respective indole and phenyl fragments. Interestingly, a conformational difference between the two independent molecules in the asymmetric unit of 3b was found. The X-ray study revealed a combination of hydrogen bonding interactions, short contacts, and π–π stacking stabilizing the specific three-dimensional packing of the molecules of 3a and 3b in the crystal structures. The three-dimensional packing of the molecules of 3b produced a zigzag layering projected along the c-axis. Both compounds effectively decreased luminol-dependent chemiluminescence in model systems with KO2-produced superoxide. They displayed opposite effects when applied in a xanthine/xanthine oxidase system. The hydrazones of 5MICA do not trigger a prooxidant effect or subsequent toxicity under conditions of iron-induced oxidative stress. The 3,4-dihydroxy-substituted derivative demonstrated excellent radical scavenging properties in all model systems, making it the lead compound for the development of compounds with combined neuroprotective and antioxidant properties.

THOUSAND-GRAIN WEIGHT 6, which is an IAA-glucose hydrolase, preferentially recognizes the structure of the indole ring

An indole-3-acetic acid (IAA)-glucose hydrolase, THOUSAND-GRAIN WEIGHT 6 (TGW6), negatively regulates the grain weight in rice. TGW6 has been used as a target for breeding increased rice yield. Moreover, the activity of TGW6 has been thought to involve auxin homeostasis, yet the details of this putative TGW6 activity remain unclear. Here, we show the three-dimensional structure and substrate preference of TGW6 using X-ray crystallography, thermal shift assays and fluorine nuclear magnetic resonance (19F NMR). The crystal structure of TGW6 was determined at 2.6 Å resolution and exhibited a six-bladed β-propeller structure. Thermal shift assays revealed that TGW6 preferably interacted with indole compounds among the tested substrates, enzyme products and their analogs. Further analysis using 19F NMR with 1,134 fluorinated fragments emphasized the importance of indole fragments in recognition by TGW6. Finally, docking simulation analyses of the substrate and related fragments in the presence of TGW6 supported the interaction specificity for indole compounds. Herein, we describe the structure and substrate preference of TGW6 for interacting with indole fragments during substrate recognition. Uncovering the molecular details of TGW6 activity will stimulate the use of this enzyme for increasing crop yields and contributes to functional studies of IAA glycoconjugate hydrolases in auxin homeostasis.

Affinity Prediction of Shikonins Towards Sirtuins and the Requisite Structural Motifs for the Selective Inhibition of SIRT2 and SIRT3

Background: Shikonin and alkannin derivatives have various pharmacological activities with unknown mechanisms of action. Sirtuins are key intracellular enzymes involved in the cell cycle and metabolism and are ideal targets of therapeutic agents. Some evidence based on recent studies indicates that shikonins are possible modulators of sirtuins. Objective: In this study, an extensive computational workflow was utilized to assess the affinity of 27 different derivatives of shikonins towards SIRT1-6 as possible molecular targets. Methods: Molecular docking and dynamics simulation studies were performed, followed by MMPBSA analysis, and the results were compared with standard and selective sirtuin inhibitors. Subsequently, the scaffold hopping approach was used to find novel and more drug-like structures. Accordingly, the pharmacophoric features of 3,4-(Methylenedioxy)cinnamoyl alkannin in SIRT2 and SIRT3 were extracted and used for screening PubChem and Mcule databases. Results: The results indicated that 3,4-(Methylenedioxy)cinnamoyl alkannin is a potent SIRT2 and SIRT3 inhibitor and even more potent than the standard sirtuin inhibitors AGK2 and selisistat. The results successfully revealed some privileged fragments for the selective inhibition of SIRT2 and SIRT3. Conclusion: An indole or benzimidazole fragment linked to basic nitrogen through an amide would be an ideal structural feature for SIRT2 inhibition, and 3-methyl-2H-pyrazolo[3,4-b]pyridine was found to be a privileged fragment for optimal inhibition of SIRT3.

One-Pot Reaction Sequence: N-Acylation/Pictet-Spengler Reaction/Intramolecular [4 + 2] Cycloaddition/Aromatization in the Synthesis of β-Carboline Alkaloid Analogues.

One-pot synthesis of tetrahydro-β-carbolines, fused with an isoindole core, was proposed starting from maleic anhydride and azomethines easily available from tryptamines and 3-(hetaryl)acroleins. This sequence includes four key steps: an acylation of the aldimine with maleic anhydride, a Pictet-Spengler cyclization, an intramolecular Diels-Alder reaction, and a concluding [1,3]-H shift. As a result, six- or seven-nuclear alkaloid-like heterocyclic systems, containing a benzo[1,2]indolizino[8,7-b]indole fragment annulated with furan, thiophene, or pyrrole, are formed in a diastereoselective manner.

Design, synthesis and biological evaluation of carbamate derivatives incorporating multifunctional carrier scaffolds as pseudo-irreversible cholinesterase inhibitors for the treatment of Alzheimer's disease

In this study, a series of carbamate derivatives incorporating multifunctional carrier scaffolds were designed, synthesized, and evaluated as potential therapeutic agents for Alzheimer's disease (AD). We used tacrine to modify the aliphatic substituent, and employed rivastigmine, indole and sibiriline fragments as carrier scaffolds. The majority of compounds exhibited good inhibitory activity for cholinesterase. Notably, compound C7 with sibiriline fragment exhibited potent inhibitory activities against human acetylcholinesterase (hAChE, IC50 = 30.35 ± 2.07 nM) and human butyrylcholinesterase (hBuChE, IC50 = 48.03 ± 6.41 nM) with minimal neurotoxicity. Further investigations have demonstrated that C7 exhibited a remarkable capacity to safeguard PC12 cells against H2O2-induced apoptosis and effectively suppressed the production of reactive oxygen species (ROS). Moreover, in an inflammation model of BV2 cells induced by lipopolysaccharide (LPS), C7 effectively attenuated the levels of pro-inflammatory cytokines. After 12 h of dialysis, C7 continued to exhibit an inhibitory effect on cholinesterase activity. An acute toxicity test in vivo demonstrated that C7 exhibited a superior safety profile and no hepatotoxicity compared to the parent nucleus tacrine. In the scopolamine-induced AD mouse model, C7 (20 mg/kg) significantly reduced cholinesterase activity in the brain of the mice. C7 was tested in a pharmacological AD mouse model induced by Aβ1-42 and attenuated memory deficits at doses as low as 5 mg/kg. The pseudo-irreversible cholinesterase inhibitory properties and multifunctional therapeutic attributes of C7 render it a promising candidate for further investigation in the treatment of AD.

Synthesis and investigation of polymers containing aniline and indole fragments

By chemical modification of copolymers of ClPA with Ani of different composition polymers containing fragments of aniline and indole have been synthesized. Their structures and compositions were determined by IR-, NMR- and UV-spectroscopy and elemental analysis methods. Morphology, electrochemical characteristics, photoluminescence, thermal stability, photoconductive properties were evaluated. The results of the thermogravimetric analysis showed that there was a significant increase in the thermal stability of these polymers. The structural changes of the modified polymers have been studied by the method of electron microscopy. It has been established that a lamellar and agglomerated surface is formed: its parameters depend on the content of aniline and indole fragments. The photoconductivity of initial copolymer films as well as of polymer films after modification was investigated. It was found that the photoconductivity of polymer films increases with the transition to polymers with a large number of indole-containing units. The obtained results indicate that modified polymers can be considered as promising materials for application in modern electronics.

Cytotoxicity of copper(I) complexes containing indole‐based thiosemicarbazones and triphenylphosphine

AbstractThe research and development department continues searching for effective and definite anticancer medications that would help eradicate cancer. The thiosemicarbazone ligands with indole fragment were utilized to create four new copper(I) complexes. Several spectral examinations and elemental analyses validated the formation of the complexes (1–4). Single crystal X‐ray diffraction (XRD) also proved that complex 4 had the expected tetrahedral structure. Complexes 1–4 were assessed for their cytotoxic property on different cell lines such as immortalized human vascular endothelial (EAhy.926), hepatocellular carcinoma (HepG‐2), and bladder cancer (T24), and kidney epithelial normal cells extracted from an African green monkey (Vero). The complexes showed reduced toxicity towards healthy Vero cells while being active in cancer cell lines. While the standard cisplatin revealed IC50 values of 26.60 and 49.90 μM, the N‐phenyl substituted complex 3 displayed a superior cytotoxic effect with IC50 values of 13.82 and 24.93 μM towards EAhy.926 and HepG‐2 cells, respectively.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

Synthesis of A-9758, an Inverse Agonist of Retinoic Acid-Related Orphan Receptor γt.

A-9758 is an inverse agonist of retinoic acid-related orphan receptor γt with well-characterized in vitro and in vivo anti-inflammatory activity. A chromatography-free decagram-scale synthesis of this compound was developed to support pre-clinical research activities. This route was designed to enable late-stage structure-activity relationship studies of the amide moiety and convergently uses a reductive alkylation sequence between indole and benzaldehyde intermediates. A key advantage of this strategy is the fact that the indole precursor can be alkylated at C2, as required for A-9758, or at C3 to provide access to an isomeric chemical series. Access to the critical indole fragment was expedited via an underutilized SnAr/reductive cyclization cascade sequence, and the benzaldehyde fragment was prepared in two steps from inexpensive 2,4-dichlorobenzoic acid.

11H-Benzo[4,5]imidazo[1,2-a]indol-11-one as a New Precursor of Azomethine Ylides: 1,3-Dipolar Cycloaddition Reactions with Cyclopropenes and Maleimides.

The possibility of generating azomethine ylides from 11H-benzo[4,5]imidazo[1,2-a]indol-11-one and amino acids is shown for the first time. Based on the cycloaddition reactions of these azomethine ylides with cyclopropenes and maleimides, cyclopropa[a]pyrrolizines, 3-azabicyclo[3.1.0]hexanes, and pyrrolo[3,4-a]pyrrolizines spiro-fused with a benzo[4,5]imidazo[1,2-a]indole fragment were synthesized. Spirocyclic compounds were obtained in moderate to good yields, albeit with poor diastereoselectivity. Density functional theory calculations were performed to obtain an insight into the mechanism of the 1,3-dipolar cycloaddition of 11H-benzo[4,5]imidazo[1,2-a]indol-11-one-derived azomethine ylides to cyclopropenes. The cytotoxic activity of some of the obtained cycloadducts against the human erythroleukemia (K562) cell line was evaluated in vitro by MTS-assay.

Synthesis, photophysical behavior in solution, aggregates, solid state and computational study of new derivatives of 2,2′-bis(indolyl)methane-triphenylamine

A series of new 2,2′-bis(indolyl)methane-triphenylamine (2,2′-BIM-TPA) derivatives were synthesized and characterized. TPA units were inserted in the indole fragment, as well as in the methylene position of the BIM to obtain systems with a high degree of torsion and intramolecular rotation. Phenyl and phenylethynyl linkers between TPA and BIM units were included in the BIM-Ph-TPA and BIM-Ph-E-TPA derivatives to extend the conjugation of the methylene substituted BIMs. The absorption and emission behavior in solution, aggregates and solid state of five 2,2′-BIM-TPA derivatives was studied. Only BIM-Ph-TPA and BIM-Ph-E-TPA showed a slight solvatochromic behavior. In THF-water mixtures, non-emissive aggregates were produced, but the concentrated solutions (1000 µM) of each compound favored the formation of emissive aggregates. It was found that water acts as a fluorescence quencher of the aggregates. Additionally, the 2,2′-BIM-TPA derivatives showed fluorescence in the solid state. The DFT computational studies allowed to confirm the highly twisted molecular geometries, to elucidate the distribution and energy of the frontier molecular orbitals (HOMO-LUMO), as well as the nature of the main electronic transitions (UV–Vis).

Design, Synthesis, and Biological Evaluation of Tetrahydro-α-carbolines as Akt1 Inhibitors That Inhibit Colorectal Cancer Cell Proliferation.

A series of densely functionalized THαCs were designed and synthesized as Akt1 inhibitors. Organocatalytic [3+3] annulation between indolin-2-imines 1 and nitroallylic acetates 2 provided rapid access to this pharmacologically interesting framework. In vitro kinase inhibitory abilities and cytotoxicity assays revealed that compound 3 af [(3S*,4S*)-4-(4-bromo-2-fluorophenyl)-9-methyl-3-nitro-1-tosyl-2,3,4,9-tetrahydro-1H-pyrido[2,3-b]indole] was the most potent Akt1 inhibitor, and mechanistic study indicated that compound 3 af suppressed the proliferation of colorectal cancer cells via inducing apoptosis and autophagy. Molecular docking suggested that the indole fragment of 3 af was inserted into the hydrophobic pocket of Akt1 protein, and the H-bond between 3 af and residue Lys179 also contributed to the stable binding. This article provides an efficient strategy to design and synthesize biologically important compounds as novel Akt1 inhibitors.

Роль состояний переноса заряда "лиганд-металл" в процессах возбуждения люминесценции индолкарбоксилатов европия

The luminescence excitation energy transfer in europium and terbium indole-3-carboxylates, indole-3-acetates and indole-3-propionates as well as ternary indolecarboxylates containing 1,10-phenanthroline and 2,2'-bipyridine molecules have been studied. The luminescence excitation spectra, the lifetimes of the 5D0 (Eu3+) and 5D4 (Tb3+) states, and the luminescence intensity are analyzed. The decisive role of ligand-metal charge transfer (LMCT) states in the quenching of the luminescence of europium aromatic carboxylates containing a π-excessive pyrrole or indole fragment is demonstrated. Most europium compounds are characterized by quenching due to the depopulation of the 5D0 state of the Eu3+ ion through the low-energy LMCT state. But in some ternary compounds, the LMCT state being of higher energy participates in the nonradiative depopulation of the excited electronic states of the ligand.

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The luminescence excitation energy transfer in europium and terbium indole-3-carboxylates, indole-3-acetates and indole-3-propionates as well as ternary indolecarboxylates containing 1,10-phenanthroline and 2,2'-bipyridine molecules have been studied. The luminescence excitation spectra, the lifetimes of the 5D0 (Eu3+) and 5D4 (Tb3+) states, and the luminescence intensity are analyzed. The decisive role of ligand-metal charge transfer (LMCT) states in the quenching of the luminescence of europium aromatic carboxylates containing a π-excessive pyrrole or indole fragment is demonstrated. Most europium compounds are characterized by quenching due to the depopulation of the 5D0 state of the Eu3+ ion through the low-energy LMCT state. But in some ternary compounds, the LMCT state being of higher energy participates in the nonradiative depopulation of the excited electronic states of the ligand.